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Cited by 151Autophagy in Disease and TherapyAlzheimer's disease research and treatmentsMitochondrial Function and Pathology

The role of mitophagy in the regulation of mitochondrial energetic status in neurons

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Han, Sinsuk, Zhang, Mingyang, Jeong, Yu Young, Margolis, David J., Cai, Qian·2021·Autophagy
DOI 10.1080/15548627.2021.1907167PMC PMC8726713
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Abstract

Mitochondria are the main cellular energy powerhouses and supply most of the energy in the form of ATP to fuel essential neuronal functions through oxidative phosphorylation (OXPHOS). In Alzheimer disease (AD), metabolic and mitochondrial disruptions are an early feature preceding any histopathological and clinical manifestations. Mitochondrial malfunction is also linked to synaptic defects in early AD. Mitophagy serves as a key cellular quality control mechanism involving sequestration of damaged mitochondria within autophagosomes and their subsequent degradation in lysosomes. However, it remains largely unknown whether mitophagy is involved in the regulation of energy metabolism in neurons, and if so, whether metabolic deficiency in AD is attributed to mitophagy dysfunction. Here we reveal that mitophagy is broadly activated in metabolically enhanced neurons upon OXPHOS stimulation, which sustains high energetic activity by increasing mitochondrial turnover and hence facilitating mitochondrial maintenance. Unexpectedly, in AD-related mutant HsAPP Tg mouse brains, early stimulation of OXPHOS activity fails to correct energy deficits but exacerbates synapse loss as a consequence of mitophagy failure. Excitingly, lysosomal enhancement in AD neurons restores impaired metabolic function by promoting elimination of damaged mitochondria, protecting against synaptic damage in AD mouse brains. Taken together, we propose a new mechanism by which mitophagy controls bioenergetic status in neurons, furthering our understanding of the direct impact of mitophagy defects on AD-linked metabolic deficits and shedding light on the development of novel therapeutic strategies to treat AD by the early stimulation of mitochondrial metabolism combined with elevation of lysosomal proteolytic activity.Abbreviations: AD: Alzheimer disease; Aβ: amyloid-β; APP: amyloid beta precursor protein; AV: autophagic vacuole; CHX: cycloheximide; CYCS: cytochrome c, somatic; DIV: days in vitro; FRET: Förster resonance energy transfer; Gln, glutamine; LAMP1: lysosomal associated membrane protein 1; LE: late endosome; Mito: mitochondria; Δψm: mitochondrial membrane potential; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; SQSTM1/p62: sequestosome 1; RHEB: Ras homolog, mTORC1 binding; ROS: reactive oxygen species; STX1: syntaxin 1; SYP: synaptophysin; Tg: transgenic; TMRE: tetramethylrhodamine ethyl ester; TEM: transmission electron microscopy; WT: wild type

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  • Impaired brain energy metabolism is an early pathological manifestation of neurodegenerative diseases including Alzheimer's disease.

    “Impaired brain energy metabolism serves as an early pathological manifestation of neurodegenerative diseases, including Alzheimer's disease (AD) [1, 2].”

    From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [2]

    The Introduction (page unavailable) says that AD patients show early metabolic deficits associated with impaired mitochondrial function, before histopathological or clinical abnormalities appear. The Discussion mentions other age-related neurodegenerative diseases but does not say that impaired energy metabolism is an early manifestation of those diseases generally. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Han, S., Zhang, M., Jeong, Y. Y., Margolis, D. J., & Cai, Q.
Affiliations
Rutgers, The State University of New Jersey (US)
Corresponding author
Cai, Qian
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2021-04-05
Volume
17
Issue
12
Pages
4182-4201
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.1080/15548627.2021.1907167
PMC
PMC8726713
OpenAlex
W3139177424
Cited by
151
References
20
Citations by year
2026: 26 · 2025: 43 · 2024: 28 · 2023: 35 · 2022: 13 · 2021: 5
FWCI
14.33
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • Figshare (cc-by)
Funders
  • National Institute of General Medical Sciences (R01GM135326)
  • National Institute of Neurological Disorders and Stroke (R01NS089737)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
mitophagy, mitochondrial bioenergetics, neurons, Alzheimer's disease, oxidative phosphorylation, mitochondrial turnover, lysosomal degradation, synaptic loss, APP transgenic mice, lysosomal proteolysis, mitochondrial quality control
MeSH terms
Alzheimer Disease, Animals, Autophagy, Mitochondria, Neurons, Amyloid beta-Peptides, Mice, Mitophagy

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