A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering

To, Tsz-Leung; Cuadros, Alejandro M.; Shah, Hardik; Hung, Wendy H. W.; Yang, Li; Kim, Sharon; Rubin, Daniel H. F.; Boe, Ryan H.; Rath, Sneha; Eaton, John K.; Piccioni, Federica; Goodale, Amy; Kalani, Zohra; Doench, John G.; Root, David E.; Schreiber, Stuart L.; Vafai, Scott B.; Mootha, Vamsi K.

doi:10.1016/j.cell.2019.10.032

Cited by 120 publications

(105 citation statements)

References 90 publications

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Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

“…By applying a genome-wide CRISPR screening on human K562 chronic myeloid leukemia cells concomitantly treated with oligomycin, an inhibitor of complex V, Mootha and colleagues identified a series of both synthetic lethal mutants and suppressors showing that complex I mutations can alleviate complex V dysfunction [ 58 ]. Mechanistically, concomitant inhibition of complexes I and V was accompanied by an increased reductive carboxylation of α-ketoglutarate [ 58 ]. Experimental depletion of cytosolic NADPH, known to drive reductive pathways, suppressed the protective effect of complex I loss against complex V inactivation, thus supporting the role of reductive metabolism in these effects [ 58 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

“…Mechanistically, concomitant inhibition of complexes I and V was accompanied by an increased reductive carboxylation of α-ketoglutarate [ 58 ]. Experimental depletion of cytosolic NADPH, known to drive reductive pathways, suppressed the protective effect of complex I loss against complex V inactivation, thus supporting the role of reductive metabolism in these effects [ 58 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

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Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

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Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

See 1 more Smart Citation

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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“…1a). Despite abundant pharmacological, genetic, and clinical data demonstrating that perturbation of different OXPHOS complexes (referred to in shorthand as complexes) produce distinct cellular adaptations 7,8 , the importance of each complex in shaping mtDNA mutation patterns in cancer is unknown. Because mtDNA is not commonly targeted by exome sequencing panels, prior analyses of mtDNA mutations have relied on cohorts profiled with whole genome sequencing, with consequently diminished statistical power to detect recurrent patterns of mutations relative to exome sequencing studies 8 .…”

Section: Introductionmentioning

confidence: 99%

Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

Gorelick

Kim

Chatila

et al. 2020

Preprint

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Mitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor lineages. Loss-of-function mutations accumulate at an elevated rate specifically in Complex I, and often arise at specific homopolymeric hotspots. In contrast, Complex V is depleted of all non-synonymous mutations, suggesting that mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

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“…Indeed, whilst differentiated cells with high energy demand, such as neurons, rely on aerobic ATP generation via OXPHOS, the abundance of glucose in standard cell culture conditions allows cells to generate sufficient levels of ATP via glycolysis. This decreased reliance on mitochondrial respiration could then mask an underlying viability defect 11 .…”

mentioning

confidence: 99%

Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

Sedlackova

Otten

Scialò

et al. 2020

Preprint

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Autophagy is an essential catabolic process that promotes clearance of surplus or damaged intracellular components 1 . As a recycling process, autophagy is also important for the maintenance of cellular metabolites during periods of starvation 2 . Loss of autophagy is sufficient to cause cell death in animal models and is likely to contribute to tissue degeneration in a number of human diseases including neurodegenerative and lysosomal storage disorders 3-7 . However, it remains unclear which of the many cellular functions of autophagy primarily underlies its role in cell survival. Here we have identified a critical role of autophagy in the maintenance of nicotinamide adenine dinucleotide (NAD + /NADH) levels. In respiring cells, loss of autophagy caused NAD(H) depletion resulting in mitochondrial membrane depolarisation and cell death. We also found that maintenance of NAD(H) is an evolutionary conserved function of autophagy from yeast to human cells. Importantly, cell death and reduced viability of autophagy-deficient animal models can be partially reversed by supplementation with an NAD(H) precursor. Our study provides a mechanistic link between autophagy and NAD(H) metabolism and suggests that boosting NAD(H) levels may be an effective intervention strategy to prevent cell death and tissue degeneration in human diseases associated with autophagy dysfunction.Macroautophagy, hereinafter autophagy, is a cellular trafficking pathway mediated by the formation of double-membraned vesicles called autophagosomes, which ultimately fuse with lysosomes, where their cargo is degraded. By sequestering and clearing dysfunctional cellular components, such as protein aggregates and damaged organelles, autophagy maintains cellular homeostasis whilst also providing metabolites and energy during periods of starvation. Studies using a range of laboratory models from yeast to mammals have established that autophagy is essential for cellular and organismal survival. For example, inducible knockout of core autophagy genes, such as Atg5, results in cell death and tissue degeneration in adult mice 3,8,9 . However, autophagy-deficient cells such as Atg5 -/mouse embryonic fibroblasts (MEFs) are viable in cell culture, which hinders in vitro studies of the mechanisms leading to cell death [8][9][10] . We hypothesized that this apparent discrepancy between the requirement for functional autophagy in vivo and in vitro could be due to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis. Indeed, whilst differentiated cells with high energy demand, such as neurons, rely on aerobic ATP generation via OXPHOS, the abundance of glucose in standard cell culture conditions allows cells to generate sufficient levels of ATP via glycolysis. This decreased reliance on mitochondrial respiration could then mask an underlying viability defect 11 .A well-established strategy to reverse cellular reliance on energy generation via aerobic glycolysis and promote mitochondrial OXPHOS, is to replace glucose, the major carbon source in tissu...

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A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering

Cited by 120 publications

References 90 publications

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

Autophagy promotes cell and organismal survival by maintaining NAD(H) pools

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