Mitochondrial and metabolic dysfunction in ageing and age-related diseases

In the paper

“and patients with Alzheimer disease-related pathology have reduced levels of mt-ND1 methylation116.”

What the sources say

• Supported

  The Discussion reports reduced MT-ND1 5mC levels in the entorhinal cortex of cases with AD-related pathology. The Results section specifies that the reduction occurred at some CpG and CHG sites in cases at Braak stages I/II and III/IV compared with controls. (LLM, conf=0.92)

  cites [116] Blanch, M., Mosquera, J. L., Ansoleaga, B., Ferrer, I. & Barrachina, M. Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease. Am. J. Pathol. 186, 385–397 (2016). source

In the paper

“Furthermore, mtDNA methylation is disturbed by environmental and other factors, such as traffic-derived elemental carbon105, maternal smoking106, endogenous metabolites107, cell senescence108 and ageing109.”

What the sources say

• Partly supported

  The Discussion reports an association between prenatal PM2.5 exposure and placental mtDNA methylation, particularly in the first trimester. The paper does not report an association specifically for traffic-derived elemental carbon; its mention of elemental carbon is in a reference to an exposure-modeling study. Citation 105 attaches to elemental carbon, so the other factors in the sentence are not assessed here. (LLM, conf=0.86)

  cites [105] Janssen, B. G. et al. Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment: an ENVIRONAGE birth cohort study. Epigenetics 10, 536–544 (2015). sourceExperimental — accuracy not yet measured
• Supported

  Citation 106 is attached specifically to maternal smoking, not to the other factors listed. The Discussion (page not provided) reports mtDNA methylation changes in placenta and foreskin associated with maternal smoking during pregnancy. (LLM, conf=0.92)

  cites [106] Armstrong, D. A. et al. Maternal smoking during pregnancy is associated with mitochondrial DNA methylation. Environ. Epigenetics 2, dvw020 (2016). source
• Supported

  Citation 107 is attached to the endogenous-metabolites example, not the other factors in the sentence. The Bovine Retinal Endothelial Cells section reports that high glucose increased mtDNA methylation, supporting glucose as an example of a metabolite that alters it; the study does not establish the effect for metabolites generally. No page number is available in our copy. (LLM, conf=0.87)

  cites [107] Mishra, M. & Kowluru, R. A. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy. Investig. Ophthalmol. Vis. Sci. 56, 5133–5142 (2015). source

In the paper

“Hence, regulation of energy metabolism by environmental variations and excessive levels of the by-product reactive oxygen species (ROS) might be associated with age-related metabolic diseases through constitutive changes in mitochondrial oxidative phosphorylation (OXPHOS), that ultimately lead to mitochondrial dysfunction.”

In the paper

“Although the mechanisms behind calorie restriction-driven longevity extension are still poorly understood, mitochondrial physiology is involved in the beneficial effects of calorie restriction in budding yeast11 and Caenorhabditis elegans12, as well as in mammals13.”

What the sources say

• Not checked yetcites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source
• Not checked yetcites [12] Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007). source
• Not checked yetcites [13] Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005). source

In the paper

“Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases.”

In the paper

“Ageing and age-related diseases are tightly related to an imbalance in energy supply and demand.”

In the paper

“Mitochondrial dysfunction can lead to severe impairment of cellular energy conversion, especially in tissues that rely heavily on chemical energy generated by mitochondria throughout life9.”

What the sources say

• Not checked yetcites [9] Chinnery, P. F. Mitochondrial disease in adults: what’s old and what’s new? EMBO Mol. Med. 7, 1503–1512 (2015). source

In the paper

“This imbalance might be alleviated by various interventions, including physical activity, calorie restriction and agents such as metformin, resveratrol and rapamycin10.”

What the sources say

• Not checked yetcites [10] Gonzalez-Freire, M. et al. The road ahead for health and lifespan interventions. Ageing Res. Rev. 59, 101037 (2020). source

In the paper

“Mitochondrial morphology and dynamics, which undergo several changes in the neurons of C. elegans during ageing21, are also affected by IIS.”

What the sources say

• Not checked yetcites [21] Morsci, N. S., Hall, D. H., Driscoll, M. & Sheng, Z. H. Age-related phasic patterns of mitochondrial maintenance in adult Caenorhabditis elegans neurons. J. Neurosci. 36, 1373–1385 (2016). source

In the paper

“accompanied by increased expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) as well as proteins involved in OXPHOS26.”

What the sources say

• Not checked yetcites [26] Brown-Borg, H. M., Johnson, W. T. & Rakoczy, S. G. Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice. Age 34, 43–57 (2012). source

In the paper

“Importantly, this increase in ROS production was observed without any detectable adverse effect in mtDNA integrity and oxidative protein damage19.”

What the sources say

• Not checked yetcites [19] Brys, K., Castelein, N., Matthijssens, F., Vanfleteren, J. R. & Braeckman, B. P. Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans. BMC Biol. 8, 91 (2010). source

In the paper

“Decreased clearance of accumulating damaged organelles, such as mitochondria, has been highly associated with ageing and age-associated diseases34 and might explain some of the beneficial effects that mTOR inhibition has on lifespan extension.”

What the sources say

• Not checked yetcites [34] Guo C., Kroemer, G. & Kepp, O. Mitophagy: an emerging role in aging and age-associated diseases. Front. Cell Dev. Biol. 8, 200 (2020). source

In the paper

“Expression of genes with protein products involved in key metabolic processes, such as glycolysis, the TCA cycle, β-oxidation and OXPHOS were increased in 2.5–3.0-year-old FIRKO mice compared with age-matched control mice28.”

What the sources say

• Not checked yetcites [28] Katic, M. et al. Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice. Aging Cell 6, 827–839 (2007). source

In the paper

“AMPK is believed to regulate the autophagic turnover of dysfunctional mitochondria through initiation of mitophagy by phosphorylation and activation of the pro-mitophagic factor UNC51-like kinase 1 (ULK1)42.”

What the sources say

• Not checked yetcites [42] Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011). source

In the paper

“Experiments in mice with a reduced ATP to AMP ratio in skeletal muscle showed an increase of mitochondrial biogenesis via AMPK induction of PGC1α expression40.”

What the sources say

• Not checked yetcites [40] Zong, H. et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl Acad. Sci. USA 99, 15983–15987 (2002). source

In the paper

“Manipulation of a gene involved in mitophagy, dct-1, a nematode orthologue of the mammalian receptors NIX and BNIP3L22, also shortens lifespan in DAF-2 mutants22.”

What the sources say

• Not checked yetcites [22] Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015). source

In the paper

“Nevertheless, the mTORC1 complex is required for PGC1α binding to the transcription factor Ying Yang 1, which induces expression of nuclear-encoded mitochondrial genes35.”

What the sources say

• Not checked yetcites [35] Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex. Nature 450, 736–740 (2007). source

In the paper

“Interestingly, the same phenotype was not observed when the insulin receptor was disrupted in liver, adipose and muscle tissues in adult mice29, denoting the complex role of the mammalian IIS pathway.”

What the sources say

• Not checked yetcites [29] Merry, T. L. et al. Impairment of insulin signalling in peripheral tissue fails to extend murine lifespan. Aging Cell 16, 761–772 (2017). source

In the paper

“The detected increase in respiratory capacity in DAF-2 mutants, contrary to what was observed in adult wild-type N2 worms, is in agreement with findings showing increased mitochondrial ROS production19.”

What the sources say

• Not checked yetcites [19] Brys, K., Castelein, N., Matthijssens, F., Vanfleteren, J. R. & Braeckman, B. P. Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans. BMC Biol. 8, 91 (2010). source

In the paper

“Moreover, mitophagy is enhanced in DAF-2 mutants22”

What the sources say

• Not checked yetcites [22] Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015). source

In the paper

“Additionally, a low dose of rapamycin extended lifespan in a mouse model of mtDNA depletion syndrome38.”

What the sources say

• Not checked yetcites [38] Siegmund, S. E. et al. Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. Hum. Mol. Genet. 26, 4588–4605 (2017). source

In the paper

“In the long-lived Ames dwarf mice and growth hormone receptor knockout (GHR-KO) mice, which develop defects in the GH–IGF1 signalling pathway, mitochondrial bioenergetics is markedly improved. This improvement was demonstrated by the metabolic shift to β-oxidation, increased oxygen consumption rate and decreased respiratory quotient25”

What the sources say

• Not checked yetcites [25] Westbrook, R., Bonkowski, M. S., Strader, A. D., & Bartke, A. Alterations in oxygen consumption respiratory quotient and heat production in long-lived GHRKO and Ames dwarf mice and short-lived bGH transgenic mice. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 443–451 (2009). source

In the paper

“exposure to mitophagy modulators increases lifespan in worms23,24.”

What the sources say

• Not checked yetcites [23] Fang, E. F. et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 7, 46208 (2017). source
• Not checked yetcites [24] Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016). source

In the paper

“Mitochondrial sirtuins also control mitochondrial physiology51.”

What the sources say

• Not checked yetcites [51] Verdin, E., Hirschey, M. D., Finley, L. W. S. & Haigis, M. C. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 35, 669–675 (2010). source

In the paper

“Moreover, SIRT1 regulates mitochondrial physiology by deacetylating and activating PGC1α and FOXO49,50, allowing control over a broad range of mitochondrial physiology.”

What the sources say

• Not checked yetcites [49] Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004). source
• Not checked yetcites [50] Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005). source

In the paper

“Interestingly, SIRT3 has been suggested to be the mediator of some of the longevity benefits of calorie restriction through its targeting and deacetylation of mitochondrial proteins55.”

What the sources say

• Not checked yetcites [55] Someya, S. et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802–812 (2010). source

In the paper

“Research findings in multiple species question the role of oxidative stress on mtDNA mutagenesis60.”

What the sources say

• Not checked yetcites [60] Kauppila, T. E. S., Kauppila, J. H. K. & Larsson, N. G. Mammalian mitochondria and aging: an update. Cell Metab. 25, 57–71 (2017). source

In the paper

“Therefore, decreased AMPK activity might be a contributor to the reduced mitochondrial function and dynamics observed during ageing45.”

What the sources say

• Not checked yetcites [45] Reznick, R. M. et al. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 5, 151–156 (2007). source

In the paper

“In rodents, the age-dependent decline in NAD+ levels decreases SIRT1 activity, ultimately affecting mitochondrial homeostasis48.”

What the sources say

• Not checked yetcites [48] Gomes, A. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). source

In the paper

“In response to calorie restriction, the yeast NAD biosynthetic gene that catalyses the first and rate-limiting step in NAD+ biosynthesis, PNC1, is induced46.”

What the sources say

• Not checked yetcites [46] Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction and stress. Nature 423, 181–185 (2003). source

In the paper

“Moreover, work on C. elegans showed that deficient mitochondrial dynamics are sufficient to block AMPK-mediated and calorie restriction-mediated increases in longevity44”

What the sources say

• Not checked yetcites [44] Weir, H. J. et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab. 26, 884–896.e5 (2017). source

In the paper

“Under mitochondrial stress, fission is activated by AMPK-mediated phosphorylation of mitochondrial fission factor, facilitating the removal of damaged mitochondria43.”

What the sources say

• Not checked yetcites [43] Toyama, E. et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016). source

In the paper

“Inherited mtDNA and nuclear DNA determine the energetic capacity of an individual during the individual’s lifetime62.”

What the sources say

• Not checked yetcites [62] Wallace, D. C. The human mitochondrion and pathophysiology of aging and age-related diseases. in Molecular Biology of Aging 1st edn (eds. Guarente, L., Partridge, L. & Wallace, D. C.) 1–38 (Cold Spring Harbor Laboratory Press, 2008).

In the paper

“The build-up of senescent cells is considered a driver of the ageing process90.”

What the sources say

• Not checked yetcites [90] Campisi, J. & D’Adda Di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007). source

In the paper

“Additionally, studies conducted in animal models and cells derived from people affected by xeroderma pigmentosum and Cockayne syndrome found decreased SIRT1 activity and persistent PARP activation due to unrepaired DNA damage.”

What the sources say

• Not checked yetcites [85] Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014). source
• Not checked yetcites [86] Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab. 20, 840–855 (2014). source

In the paper

“For example, defects in mitochondrial OXPHOS are observed in the early stages of cellular senescence91–93.”

What the sources say

• Not checked yetcites [91] Yoon, Y. S., Byun, H. O., Cho, H., Kim, B. K. & Yoon, G. Complex II defect via down-regulation of iron-sulfur subunit induces mitochondrial dysfunction and cell cycle delay in iron chelation-induced senescence-associated growth arrest. J. Biol. Chem. 278, 51577–51586 (2003). source
• Not checked yetcites [92] Byun, H. O. et al. GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) β1-induced senescence. Exp. Cell Res. 318, 1808–1819 (2012). source
• Not checked yetcites [93] Lafargue, A. et al. Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex II dysfunction and superoxide generation. Free. Radic. Biol. Med. 108, 750–759 (2017). source

In the paper

“Supporting this hypothesis, DNA repair-deficient premature ageing diseases, such as ataxia–telangiectasia (ATM), Cockayne syndrome group A and xeroderma pigmentosum group A, have been linked to changes in mitochondrial physiology, which are indicative of physiological responses to anterograde stimuli77.”

What the sources say

• Not checked yetcites [77] Scheibye-Knudsen, M., Fang, E. F., Croteau, D. L. & Bohr, V. A. Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders. Autophagy 10, 1468–1469 (2014). source

In the paper

“In addition to its critical role in organismal health and mitochondrial physiology, NAD+ is a rate-limiting metabolite for the poly(ADP-ribose) polymerases (PARPs)81, which are key DDR proteins.”

What the sources say

• Not checked yetcites [81] Chambon, P., Weill, J. D. & Mandel, P. Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem. Biophys. Res. Commun. 11, 39–43 (1963). source

In the paper

“Genomic instability in the nucleus can impact mitochondrial physiology during ageing via what is known as anterograde signalling76.”

What the sources say

• Not checked yetcites [76] Fang, E. F. et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17, 308–321 (2016). source

In the paper

“This network is crucial to cells meeting their metabolic demands through mitochondrial fission and fusion events95,98.”

What the sources say

• Not checked yetcites [95] Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010). source
• Not checked yetcites [98] Mai, S., Klinkenberg, M., Auburger, G., Bereiter-Hahn, J. & Jendrach, M. Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J. Cell Sci. 123, 917–926 (2010). source

In the paper

“Human diseases, including cardiovascular diseases110, colorectal cancer111, non-alcoholic steatohepatitis112, obesity-induced insulin resistance113 and Down syndrome114, have also been associated with changes in mtDNA methylation patterns.”

What the sources say

• Not checked yetcites [110] Baccarelli, A. A. & Byun, H. Platelet mitochondrial DNA methylation: a potential new marker of cardiovascular disease. Clin. Epigenetics 7, 44 (2015). source
• Not checked yetcites [111] Feng, S. H. I., Xiong, L., Ji, Z., Cheng, W. E. I. & Yang, H. Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer. Mol. Med. Rep. 6, 125–130 (2012).
• Not checked yetcites [112] Pirola, C. et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 62, 1356–1263 (2013). source

In the paper

“Analysis of both European126 and Asian populations127 showed that the 16189T>C substitution in the D-loop region of mtDNA is associated with obesity and T2DM.”

What the sources say

• Not checked yetcites [126] Poulton, J. et al. The presence of a common mitochondrial DNA variant is associated with fasting insulin levels in Europeans in Auckland. Diabet. Med. 19, 969–971 (2002). source
• Not checked yetcites [127] Kim, J. H. et al. The prevalence of the mitochondrial DNA 16189 variant in non-diabetic Korean adults and its association with higher fasting glucose and body mass index. Diabet. Med. 19, 681–684 (2002). source

In the paper

“Interestingly, mtDNA polymorphisms have been associated with an increased risk of metabolic diseases.”

What the sources say

• Not checked yetcites [126] Poulton, J. et al. The presence of a common mitochondrial DNA variant is associated with fasting insulin levels in Europeans in Auckland. Diabet. Med. 19, 969–971 (2002). source
• Not checked yetcites [127] Kim, J. H. et al. The prevalence of the mitochondrial DNA 16189 variant in non-diabetic Korean adults and its association with higher fasting glucose and body mass index. Diabet. Med. 19, 681–684 (2002). source
• Not checked yetcites [128] Tanaka, M. et al. Women with mitochondrial haplogroup N9a are protected against metabolic syndrome. Diabetes 56, 518–521 (2007). source

In the paper

“Furthermore, pathogenic mtDNA has also been reported to be involved in cellular senescence99.”

What the sources say

• Not checked yetcites [99] Kwon, S. M., Hong, S. M., Lee, Y. & Min, S. Metabolic features and regulation in cell senescence. BMB Rep. 52, 5–12 (2019). source

In the paper

“However, in 2011, Shock and colleagues showed that both 5-mC and hydroxymethylated (5-hmC) cytosine residues, along with DNA methyltransferase 1 (DNMT1), are present in mtDNA from human and mouse cell lines100.”

What the sources say

• Not checked yetcites [100] Shock, L. S., Thakkar, P. V., Peterson, E. J., Moran, R. G. & Taylor, S. M. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc. Natl Acad. Sci. USA 108, 3630–3635 (2011). source

In the paper

“For example, there is a decrease in the methylation of the mtDNA D-loop region in patients carrying the amyotrophic lateral sclerosis-linked superoxide dismutase 1 (SOD1) mutations115.”

What the sources say

• Not checked yetcites [115] Stoccoro, A. et al. Mitochondrial DNA copy number and D-loop region methylation in carriers of amyotrophic lateral sclerosis gene mutations. Epigenomics 10, 1431–1443 (2018). source

In the paper

“Consequently, individuals with obesity tend to oxidize lipids instead of metabolizing glucose under insulin-stimulated conditions121.”

What the sources say

• Not checked yetcites [121] Storlien, L., Oakes, N. D. & Kelley, D. E. Metabolic flexibility. Proc. Nutr. Soc. 63, 363–368 (2004). source

In the paper

“Changes in energy metabolism, especially in tissues dependent on insulin-stimulated glucose disposal124, lead to mitochondrial deregulation and increased ROS generation.”

What the sources say

• Not checked yetcites [124] Litvinova, L. S., Kirienkova, E. V., Mazunin, I. O., Vasilenko, M. A. & Fattakhov, N. S. Pathogenesis of insulin resistance in metabolic obesity. Biochem. Suppl. B Biomed. Chem. 8, 192–202 (2014).

In the paper

“Consequently, an observed decrease in fatty acid oxidation and an increase in cytosolic levels of free fatty acids ultimately lead to pathologies such as type 2 diabetes mellitus (T2DM), muscle dysfunction and insulin resistance125.”

What the sources say

• Not checked yetcites [125] Pagel-Langenickel, I., Bao, J., Pang, L. & Sack, M. N. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr. Rev. 31, 25–51 (2010). source

In the paper

“Patients with Parkinson disease have decreased methylation of the D-loop116”

What the sources say

• Not checked yetcites [116] Blanch, M., Mosquera, J. L., Ansoleaga, B., Ferrer, I. & Barrachina, M. Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease. Am. J. Pathol. 186, 385–397 (2016). source

In the paper

“In one study, insulin resistance in older patients (mean age 70 ± 2 years) was associated with decreased mitochondrial ATP production and modifications in mitochondrial OXPHOS123.”

What the sources say

• Not checked yetcites [123] Petersen, K. F. et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300, 1140–1142 (2003). source

In the paper

“Epidemiological studies have suggested that the presence of NAFLD might be a precursor to the development of other conditions, such as insulin resistance and T2DM151.”

What the sources say

• Not checked yetcites [151] Valenti, L., Bugianesi, E., Pajvani, U. & Targher, G. Nonalcoholic fatty liver disease: cause or consequence of type 2 diabetes? Liver Int. 36, 1563–1579 (2016). source

In the paper

“Long-term and chronic exposure to hyperglycaemia can cause desensitization and even depletion of β-cells, making them unable to secrete insulin due to the depletion of intracellular reserves141.”

What the sources say

• Not checked yetcites [141] Robertson, R., Harmon, J., Tran, P., Tanaka, Y. & Takahashi, H. Glucose toxicity in β-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581–587 (2003). source

In the paper

“While there is no evidence for mitochondrial depletion in β-cells from patients with T2DM, the mitochondrial density volume is considerably higher in islets from patients with T2DM than in islets from those without T2DM, with both morphological and functional abnormalities that have not been observed in β-cells from control individuals143.”

What the sources say

• Not checked yetcites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

In the paper

“Data published in 2017 regarding 31P-magnetic resonance spectroscopy from individuals without diabetes mellitus in the Baltimore Longitudinal Study of Aging (BLSA) showed that a higher impairment of mitochondrial capacity is associated with greater insulin resistance and a higher likelihood of prediabetes than in participants classified as being ‘normal’ according to the American Diabetes Ass”

What the sources say

• Not checked yetcites [138] Fabbri, E. et al. Insulin resistance is associated with reduced mitochondrial oxidative capacity measured by 31P-magnetic resonance spectroscopy in participants without diabetes from the Baltimore Longitudinal Study of Aging. Diabetes 66, 170–176 (2017). source

In the paper

“Individuals with prediabetes and T2DM have an increased risk of presenting with hyperglycaemia associated with a progressive rise in oxidative stress and altered mitochondrial morphology135.”

What the sources say

• Not checked yetcites [135] Bhansali, S., Bhansali, A., Walia, R., Saikia, U. N. & Dhawan, V. Alterations in mitochondrial oxidative stress and mitophagy in subjects with prediabetes and type 2 diabetes mellitus. Front. Endocrinol. 8, 347 (2017). source

In the paper

“In addition, PGC1α silencing in healthy human islets resulted in reduced insulin secretion145, a phenomenon also found in patients with a common mtDNA variant in mitochondrial transcription factor B1 (TFB1M)146.”

What the sources say

• Not checked yetcites [146] Koeck, T. et al. A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes. Cell Metab. 13, 80–91 (2011). source

In the paper

“Additionally, analysis of insulin-secreting pancreatic β-cells and islets from patients with T2DM showed alterations in mitochondrial physiology, such as hyperpolarization of the mitochondrial membrane and decreased activities of the enzymes glycerol phosphate dehydrogenase, pyruvate carboxylase and succinyl-CoA–3-ketoacid-CoA transferase147,148.”

What the sources say

• Not checked yetcites [147] Goehring, I. et al. Plasma membrane potential oscillations in insulin secreting Ins-1 832/13 cells do not require glycolysis and are not initiated by fluctuations in mitochondrial bioenergetics. J. Biol. Chem. 287, 15706–15717 (2012). source
• Not checked yetcites [148] MacDonald, M. J. et al. Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes. Diabetologia 52, 1087–1091 (2009). source

In the paper

“In addition, PGC1α silencing in healthy human islets resulted in reduced insulin secretion145, a phenomenon also found in patients with a common mtDNA variant in mitochondrial transcription factor B1 (TFB1M)146.”

What the sources say

• Not checked yetcites [145] Ling, C. et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51, 615–622 (2008). source

In the paper

“Impairment in β-cell metabolism observed in islets from donors with T2DM and in β-cells from a mouse model of human neonatal diabetes upon exposure to hyperglycaemia support the notion that inhibition of mitochondrial metabolism is central to β-cell dysfunction143,144.”

What the sources say

• Not checked yetcites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source
• Not checked yetcites [144] Brereton, M. F. et al. Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells. Nat. Commun. 7, 13496 (2016). source

In the paper

“The association between mitochondrial dysfunction and T2DM is also supported by the downregulation of genes involved in oxidative metabolism and under the control of PGC1α in the skeletal muscle of patients with T2DM140.”

What the sources say

• Not checked yetcites [140] Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003). source

In the paper

“Furthermore, decreased mitochondrial respiration was found in first-degree relatives of individuals with T2DM139.”

What the sources say

• Not checked yetcites [139] Phielix, E. et al. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57, 2943–2949 (2008). source

In the paper

“Patients with NAFLD present with decreased ETC complex activity153,154 and a fatty liver-associated decrease in SIRT3 activity, which leads to hyperacetylation of mitochondrial proteins and mitochondrial dysfunction155.”

What the sources say

• Not checked yetcites [153] Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015). source
• Not checked yetcites [154] Pérez-Carreras, M. et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 999–1007 (2003). source

In the paper

“Lipid accumulation in hepatocytes has been linked to insulin resistance and the development of T2DM158.”

What the sources say

• Not checked yetcites [158] Kotronen, A., Seppälä-Lindroos, A., Bergholm, R. & Yki-Järvinen, H. Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome. Diabetologia 51, 130–138 (2008). source

In the paper

“In agreement with reduced insulin secretion, PGC1α expression was found to be reduced by 90% in islets from patients with T2DM.”

What the sources say

• Not checked yetcites [145] Ling, C. et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51, 615–622 (2008). source

In the paper

“In addition, the A8890G mtDNA mutation was found in a juvenile patient with the metabolic syndrome phenotype131.”

What the sources say

• Not checked yetcites [131] Ye, W., Chen, S., Jin, S. & Lu, J. A novel heteroplasmic mitochondrial DNA mutation, A8890G, in a patient with juvenile-onset metabolic syndrome: a case report. Mol. Med. Rep. 8, 1060–1066 (2013). source

In the paper

“Patients with NAFLD present with decreased ETC complex activity153,154 and a fatty liver-associated decrease in SIRT3 activity, which leads to hyperacetylation of mitochondrial proteins and mitochondrial dysfunction155.”

What the sources say

• Not checked yetcites [155] Kendrick, A. A. et al. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem. J. 433, 505–514 (2011). source

In the paper

“It is likely that the lack of oxidative capacity to overcome the excess fatty acids that are transported to the liver during conditions such as obesity might have a vital role in the progression of NAFLD accompanied by insulin resistance159.”

What the sources say

• Not checked yetcites [159] Pessayre, D. & Fromenty, B. NASH: a mitochondrial disease. J. Hepatol. 42, 928–940 (2005). source

In the paper

“Closely related to ROS production, the mitochondrial Src homology–collagen (Shc) adaptor protein p66Shc might be the link between ageing and metabolic and cardiovascular diseases.”

In the paper

“These biochemical changes are associated with ultrastructural abnormalities that indicate an impaired OXPHOS.”

In the paper

“Mutant p66Shc−/− mice have been reported to be resistant to oxidative stress and to have an increased lifespan185, as well as reduced age-dependent endothelial dysfunction186.”

What the sources say

• Not checked yetcites [186] Francia, P. et al. Deletion of p66Shc gene protects against age-related endothelial dysfunction. Circulation 110, 2889–2895 (2004). source

In the paper

“In humans, the first evidence for a role of p66Shc in diabetes mellitus came with the finding that patients with T2DM have increased expression of p66Shc in circulating peripheral blood mononuclear cells190.”

What the sources say

• Not checked yetcites [190] Pagnin, E. et al. Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. J. Clin. Endocrinol. Metab. 90, 1130–1136 (2005). source

In the paper

“Mitochondrial dysfunction is a hallmark of many chronic inflammatory diseases193, including those caused by the innate immune response194.”

What the sources say

• Not checked yetcites [193] Dela Cruz, C. S. & Kang, M. J. Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. Mitochondrion 41, 37–44 (2018). source
• Not checked yetcites [194] Chaplin, D. D. Overview of the immune response. J. Allergy Clin. Immunol. 125, S3–S23 (2010). source

In the paper

“Finally, a reduction in mtDNA copy number has also been observed in cardiovascular risk factors independent of atherosclerosis, such as hyperlipidaemia179.”

What the sources say

• Not checked yetcites [179] Liu, C. S. et al. Alteration of the copy number of mitochondrial DNA in leukocytes of patients with hyperlipidemia. Ann. N. Y. Acad. Sci. 1042, 70–75 (2005). source

In the paper

“In line with these arguments, both hepatic insulin resistance and simple steatosis were already established in mice fed a high-fat diet for 8 weeks, well before changes in mitochondrial bioenergetics became evident166,167.”

What the sources say

• Not checked yetcites [166] Patterson, R. E. et al. Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity. Am. J. Physiol. Endocrinol. Metab. 310, E484–E494 (2016). source
• Not checked yetcites [167] Satapati, S. et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J. Lipid Res. 53, 1080–1092 (2012). source

In the paper

“Interestingly, in work performed in humans with NAFLD, a rapid elevation of liver levels of triglycerides was observed and is associated with stimulation of mitochondrial oxidative function165, suggesting a compensatory stimulation of mitochondrial β-oxidation.”

What the sources say

• Not checked yetcites [165] Sunny, N. E., Parks, E. J., Browning, J. D. & Burgess, S. C. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14, 804–810 (2011). source

In the paper

“Electron microscopy analysis has shown abnormal ultrastructural lesions in mitochondria from human aortic atherosclerotic lesions, compared with mitochondria from normal parts of the aortic intima174.”

What the sources say

• Not checked yetcites [174] Sobenin, I. A., Sazonova, M. A., Postnov, A. Y., Bobryshev, Y. V. & Orekhov, A. N. Changes of mitochondria in atherosclerosis: possible determinant in the pathogenesis of the disease. Atherosclerosis 227, 283–288 (2013). source

In the paper

“The health benefits provided by rapamycin, however, seem to be tissue-specific.”

In the paper

“Moreover, mitochondrially-derived ROS are a key component of the immune system.”

In the paper

“Daily voluntary exercise also ameliorates progeroid mouse phenotypes, such as locomotor activity, alopecia and kyphosis, and the deregulated proteomic profiles in muscle and brain in mtDNA mutator mice216.”

What the sources say

• Not checked yetcites [216] Ross, J. M. et al. Voluntary exercise normalizes the proteomic landscape in muscle and brain and improves the phenotype of progeroid mice. Aging Cell 18, e13029 (2019). source

In the paper

“Activation of AMPK increases mitochondrial chemical energy generation by increasing the AMP to ATP ratio236.”

What the sources say

• Not checked yetcites [236] Canto, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010). source

In the paper

“Moreover, calorie restriction stimulates mitochondrial turnover by boosting mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy221,222.”

What the sources say

• Not checked yetcites [221] Kume, S. et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest. 120, 1043–1055 (2010). source
• Not checked yetcites [222] Pardo, R. et al. Calorie restriction prevents diet-induced insulin resistance independently of PGC-1-driven mitochondrial biogenesis in white adipose tissue. FASEB J. 33, 2343–2358 (2019). source

In the paper

“Decreased mitochondrial ROS production and macromolecular oxidative damage due, in part, to mitochondrial uncoupling might also explain the benefits of calorie restriction219,220.”

What the sources say

• Not checked yetcites [219] Brand, M. D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol. 35, 811–820 (2000). source
• Not checked yetcites [220] Barja, G. Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res. Rev. 1, 397–411 (2002). source

In the paper

“Moreover, resveratrol-dependent activation of SIRT1 has also been shown to trigger mitochondrial biogenesis both in vitro and in transgenic rats with human genes for renin and angiotensinogen by inducing mRNA expression of mitochondrial biogenesis markers, such as PGC1α229.”

What the sources say

• Not checked yetcites [229] Biala, A. et al. Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes. Blood Press. 19, 196–205 (2010). source

In the paper

“By contrast, an uncontrolled release of mitochondrial components into the cytoplasm or the extracellular space due to, for example, mitochondrial dysfunction, can induce chronic inflammation, a condition associated with several diseases, such as rheumatoid arthritis, atherosclerosis, liver injury, obesity and ageing, an effect known as ‘inflammaging’.”

In the paper

“Succinate, an intermediate of the TCA cycle, is emerging as an important signalling molecule207.”

What the sources say

• Not checked yetcites [207] Mills, E. & O’Neill, L. A. J. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 24, 313–320 (2014). source

In the paper

“Among them, several polyphenols that improve mitochondrial physiology have been described223.”

What the sources say

• Not checked yetcites [223] Davinelli, S., De Stefani, D., De Vivo, I. & Scapagnini, G. Polyphenols as caloric restriction mimetics regulating mitochondrial biogenesis and mitophagy. Trends Endocrinol. Metab. 31, 536–550 (2020). source

In the paper

“Knocking out the Raptor complex in adipose tissue enhances mitochondrial respiration244, but muscle-specific knockout causes muscular dystrophy in mice36.”

What the sources say

• Not checked yetcites [244] Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008). source

In the paper

“Calorie restriction is another widely known lifestyle intervention that can prevent age-related metabolic disorders in multiple species217.”

What the sources say

• Not checked yetcites [217] Omodei, D. & Fontana, L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 585, 1537–1542 (2011). source

In the paper

“Resveratrol enhances mitochondrial biogenesis and oxidative capacity in animal models of diet-induced obesity and ageing226,227.”

What the sources say

• Not checked yetcites [226] Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). source
• Not checked yetcites [227] Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006). source

In the paper

“Also, the administration of epicatechin-rich cocoa stimulated mitochondrial biogenesis in patients with T2DM234.”

What the sources say

• Not checked yetcites [234] Taub, P. R. et al. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa. Clin. Transl. Sci. 5, 43–47 (2012). source

In the paper

“Other alarmins of mitochondrial origin, including ATP, succinate, TFAM and ROS, all induce and support inflammation by different means205.”

What the sources say

• Not checked yetcites [205] Chandel, N. S. Evolution of mitochondria as signaling organelles. Cell Metab. 22, 204–206 (2015). source

In the paper

“Knocking out the Raptor complex in adipose tissue enhances mitochondrial respiration244, but muscle-specific knockout causes muscular dystrophy in mice36.”

What the sources say

• Not checked yetcites [36] Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008). source

In the paper

“Mitophagy can also be induced by resveratrol via FOXO3 activation, which triggers the PINK1–Parkin pathway230.”

What the sources say

• Not checked yetcites [230] Kuno, A. et al. Resveratrol ameliorates mitophagy disturbance and improves cardiac pathophysiology of dystrophin-deficient mdx mice. Sci. Rep. 8, 15555 (2018). source

In the paper

“Finally, oleuropein, a polyphenol present in the leaves of fruits and olives, promotes phosphorylation and consequent activation of mitophagy-related proteins by activation of the AMPK–ULK1 pathway in a diet-induced mouse model of obesity235.”

What the sources say

• Not checked yetcites [235] Porcu, C. et al. Oleuropein induces AMPK-dependent autophagy in NAFLD mice, regardless of the gender. Int. J. Mol. Sci. 19, E3948 (2018). source

In the paper

“Punicalagin, the most abundant ellagitannin in the pomegranate fruit, stimulates mitochondrial biogenesis in cardiomyocytes from obese rats233.”

What the sources say

• Not checked yetcites [233] Cao, K. et al. Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation. Sci. Rep. 5, 14014 (2015). source

In the paper

“To some extent, this effect can be explained by the elicited mitochondrial unfolded protein response mediated by nicotinamide riboside258.”

What the sources say

• Not checked yetcites [258] Gariani, K. et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63, 1190–1204 (2016). source

In the paper

“Interestingly, a human clinical trial testing leucine–resveratrol combinations showed improved glucose homeostasis and insulin sensitivity in patients with prediabetes, suggesting that synergistic approaches might be a good alternative to treat age-associated metabolic diseases250.”

What the sources say

• Not checked yetcites [250] Zemel, M. B. Modulation of energy sensing by leucine synergy with natural sirtuin activators: effects on health span. J. Med. Food 23, 1129–1135 (2020). source

In the paper

“In humans, MitoQ improves vascular ageing in middle-aged and older adults (aged 60–79 years)286.”

What the sources say

• Not checked yetcites [286] Rossman, M. J. et al. Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 71, 1056–1063 (2018). source

In the paper

“A large body of evidence from animal studies supports NAD+-boosting therapies as a way to ameliorate a wide variety of age-related metabolic disease.”

In the paper

“Collectively, these observations suggest that this class of drugs might hold the potential to treat obesity and metabolic diseases.”

In the paper

“Systematic NAD+ decline and decreased sirtuin activity are considered among the molecular events that occur during ageing, possibly underlying the increase in age-related diseases that limit organismal lifespan251.”

What the sources say

• Not checked yetcites [251] Rajman, L., Chwalek, K. & Sinclair, D. A. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 27, 529–547 (2018). source

In the paper

“Adipose-specific Raptor knockout mice (Raptorad−/−) have a lean phenotype and are protected against diet-induced obesity, due to enhanced energy expenditure facilitated by UCP1-mediated mitochondrial uncoupling244.”

What the sources say

• Not checked yetcites [244] Polak, P. et al. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8, 399–410 (2008). source

In the paper

“Due to the central role of mitochondrial ROS and mitochondrial oxidative damage in disease, mitochondrial-targeted antioxidant therapies have been explored as potential treatments278.”

What the sources say

• Not checked yetcites [278] Silva, F. S., Simoes, R. F., Couto, R. & Oliveira, P. J. Targeting mitochondria in cardiovascular diseases. Curr. Pharm. Des. 22, 5698–5717 (2016). source

In the paper

“In 2021, positive results from a phase I clinical trial testing mitochondrial uncoupler HU6 were presented. HU6 was well tolerated without serious adverse effects, and provided additional improvements in resting energy expenditure and dose-dependent weight loss277, supporting the potential for the development of mitochondrial uncouplers for the treatment of metabolic dysfunction in humans.”

What the sources say

• Not checked yetcites [277] Rivus Pharmaceuticals. Rivus Pharmaceuticals announces positive results from phase 1 trial of lead candidate HU6, demonstrating safety, efficacy in key targets for multiple cardio-metabolic diseases. https://www.rivuspharma.com. (2021).

In the paper

“Additionally, inhibition of NAD+-consuming enzymes has been shown to be a promising approach to treat mitochondrial dysfunction in age-related metabolic dysfunction261.”

What the sources say

• Not checked yetcites [261] Gariani, K. et al. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66, 132–141 (2017). source

In the paper

“One of the first molecules to be described as having potential therapeutic benefits in obesity and metabolic diseases is the mitochondrial uncoupler 2,4-dinitrophenol (DNP)263.”

What the sources say

• Not checked yetcites [263] Tainter, M. L., Stockton, A. B. & Cutting, W. C. Use of dinitrophenol in obesity and related conditions. J. Am. Med. Assoc. 101, 1472–1475 (1933). source