|ZFIN ID: ZDB-PUB-200618-9|
Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle
Chen, Z., Berquez, M., Luciani, A.
|Source:||Cell stress 4: 147-150 (Review)|
|Registered Authors:||Chen, Zhiyong, Luciani, Alessandro|
|Keywords:||cell damage, inherited metabolic disorders, kidney tubule, metabolism, mitochondria, mitophagy, organelle quality control, oxidative stress|
|PubMed:||32548571 Full text @ Cell Stress|
Chen, Z., Berquez, M., Luciani, A. (2020) Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle. Cell stress. 4:147-150.
ABSTRACTDysregulation 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.
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