Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show con...Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show consistently low mitochondrial oxidative phosphorylation(OxPhos)capacity across organ systems.Here,we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans.Across up to 22 mouse tissues,neither mitochondrial OxPhos capacity nor mitochondrial DNA(mtDNA)density was correlated between tissues(median r=−0.01 to 0.16),indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues.Similarly,RNA sequencing(RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men(genotype-tissue expression[GTEx])showed only small to moderate coherence between some tissues,such as between brain regions(r=0.26),but not between brain–body tissue pairs(r=0.01).The mtDNA copy number(mtDNAcn)also lacked coherence across human tissues.Mechanistically,tissue-specific differences in mitochondrial gene expression were partially attributable to(i)tissue-specific activation of energy sensing pathways,including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the integrated stress response(ISR),and other molecular regulators of mitochondrial biology,and(ii)proliferative activity across tissues.Finally,we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes.These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.展开更多
Major life transitions are always difficult because change costs energy.Recent findings have demonstrated how mitochondrial oxidative phosphorylation(OxPhos)defects increase the energetic cost of living and that exces...Major life transitions are always difficult because change costs energy.Recent findings have demonstrated how mitochondrial oxidative phosphorylation(OxPhos)defects increase the energetic cost of living and that excessive integrated stress response(ISR)signaling may prevent cellular identity transitions during development.In this perspective,we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity.The energetic cost of cellular differentiation has not been directly quantified,representing a gap in knowledge.We propose that the ISR is an energetic checkpoint evolved to(i)prevent OxPhos-deficient cells from engaging in excessively costly transitions and(ii)allow ISR-positive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.展开更多
基金supported by the NIH grants(R35GM119793,R01AG066828,and R01AG086764)Baszucki Group to M.P.
文摘Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show consistently low mitochondrial oxidative phosphorylation(OxPhos)capacity across organ systems.Here,we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans.Across up to 22 mouse tissues,neither mitochondrial OxPhos capacity nor mitochondrial DNA(mtDNA)density was correlated between tissues(median r=−0.01 to 0.16),indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues.Similarly,RNA sequencing(RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men(genotype-tissue expression[GTEx])showed only small to moderate coherence between some tissues,such as between brain regions(r=0.26),but not between brain–body tissue pairs(r=0.01).The mtDNA copy number(mtDNAcn)also lacked coherence across human tissues.Mechanistically,tissue-specific differences in mitochondrial gene expression were partially attributable to(i)tissue-specific activation of energy sensing pathways,including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the integrated stress response(ISR),and other molecular regulators of mitochondrial biology,and(ii)proliferative activity across tissues.Finally,we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes.These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.
基金supported by grants from the NIH(R01MH119336,R01MH122706,R01AG066828,and RF1AG076821)the Wharton Fund,and the Baszucki Brain Research Fund to M.P.M.L.gratefully acknowledges support from the Templeton World Charity Foundation(TWCF0606)the Bill and Melinda Gates Foundation.
文摘Major life transitions are always difficult because change costs energy.Recent findings have demonstrated how mitochondrial oxidative phosphorylation(OxPhos)defects increase the energetic cost of living and that excessive integrated stress response(ISR)signaling may prevent cellular identity transitions during development.In this perspective,we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity.The energetic cost of cellular differentiation has not been directly quantified,representing a gap in knowledge.We propose that the ISR is an energetic checkpoint evolved to(i)prevent OxPhos-deficient cells from engaging in excessively costly transitions and(ii)allow ISR-positive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.
