Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle
Authors:Zhiyong Chen1, Marine Berquez1 and Alessandro Luciani1
1 Institute of Physiology, Mechanisms of Inherited Kidney Disorders Group, University of Zurich, 8057 Zurich, Switzerland.
Keywords:
cell damage, inherited metabolic disorders, kidney tubule, metabolism, mitochondria, mitophagy, organelle quality control, oxidative stress.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no competing interest.
Please cite this article as:
Zhiyong Chen, Marine Berquez and Alessandro Luciani (2020). Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle. Cell Stress 4(6): 147-150. doi: 10.15698/cst2020.06.222
© 2020 Chen et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
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.