Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle
| Autor: | Alessandro Luciani, Zhiyong Chen, Marine Berquez |
|---|---|
| Přispěvatelé: | University of Zurich, Luciani, Alessandro |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Physiology Cell Methylmalonic acidemia lcsh:Medicine 610 Medicine & health Mitochondrion Biology 1301 Biochemistry Genetics and Molecular Biology (miscellaneous) Biochemistry Genetics and Molecular Biology (miscellaneous) Parkin 10052 Institute of Physiology Mitophagy medicine oxidative stress 1306 Cancer Research lcsh:QH301-705.5 Zebrafish Cell damage kidney tubule lcsh:R Autophagy 1314 Physiology medicine.disease biology.organism_classification Cell biology cell damage mitochondria inherited metabolic disorders mitophagy medicine.anatomical_structure lcsh:Biology (General) 1313 Molecular Medicine 570 Life sciences biology Molecular Medicine organelle quality control metabolism |
| Zdroj: | Cell Stress, Vol 4, Iss 6, Pp 147-150 (2020) |
| ISSN: | 2523-0204 |
| DOI: | 10.15698/cst2020.06.222 |
| Popis: | Dysregulation of the mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of intermediary metabolism caused by the deficiency of methylmalonyl-CoA mutase (MMUT) — a mitochondrial enzyme that mediates the degradation of certain amino acids and lipids. The loss of MMUT activity triggers an accumulation of toxic endogenous metabolites causing severe organ dysfunctions and life-threatening complications. How MMUT deficiency instigates mitochondrial distress and tissue damage remains poorly understood. Using cell and animal-based models, we recently discovered that MMUT deficiency disables the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, impeding their delivery and subsequent dismantling by macroautophagy/autophagy-lysosome degradation systems (Luciani et al. Nat Commun. 11(1):970). This promotes an accumulation of damaged and/or dysfunctional mitochondria that spark epithelial distress and tissue damage. Using a systems biology approach based on drug-disease network perturbation modeling, we predicted targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived kidney cells and ameliorates disease-relevant phenotypes in mmut-deficient zebrafish. These results unveil a link between primary MMUT deficiency, defective mitophagy, and cell distress, offering promising therapeutic avenues for MMA and other mitochondria-related diseases. |
| Databáze: | OpenAIRE |
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