Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy
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LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, however, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1α subunit of PDH, which inhibits enzyme activity. Blocking E1α phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild-type LonP1 in the siblings' fibroblasts down-regulated phosphoE1α. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1α, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which promotes severe neurologic impairment and neurodegeneration.
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In human skeletal muscle, reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness.
“In human skeletal muscle, the reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness [162–164].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [164]
The matrix mitochondrial protease LonP1 is necessary for maintenance of mitochondrial matrix proteostasis.
“The matrix mitochondrial protease LonP1 is necessary for the maintenance of mitochondrial matrix proteostasis.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [164]
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- Authors
- Nimmo, G. A. M., Venkatesh, S., Pandey, A. K., Marshall, C. R., Hazrati, L.-N., Blaser, S., Ahmed, S., Cameron, J., Singh, K., Ray, P. N., Suzuki, C. K., & Yoon, G.
- Affiliations
- University of Toronto (CA)
- Rutgers, The State University of New Jersey (US)
- Division of Paediatric Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Karolinska Institutet (SE)
- Corresponding author
- Suzuki, Carolyn K
- Yoon, Grace
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-10-09
- Volume
- 28
- Issue
- 2
- Pages
- 290-306
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6322071
- OpenAlex
- W2897695914
- Cited by
- 40
- References
- 38
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 3
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Toronto (MC-2012-13A)
- National Institutes of Health (1R21HD008391601)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- LONP1, pyruvate dehydrogenase deficiency, mitochondrial proteostasis, neurodegeneration, cerebellar atrophy, missense mutations, consanguinity, mitochondrial dysfunction, lactate/pyruvate ratio, energy metabolism, ragged-red fibers, cytochrome c oxidase
- MeSH terms
- Alleles, Cerebellar Diseases, DNA, Mitochondrial, Homozygote, Humans, Infant, Newborn, Lactates, Male, Mutation, Pedigree, Phosphorylation, Pyruvate Dehydrogenase Complex Deficiency Disease, Neurodegenerative Diseases, Protein Subunits, Mitochondrial Proteins, ATP-Dependent Proteases, Proteolysis
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