Biology subjects

Traa, A.

Publications and source records attributed to Traa, A..

3 recordsLinked to original sources

bioRxiv2022

Exercise preserves fitness capacity during aging through AMPK and mitochondrial dynamics

Exercise is a nonpharmacological intervention that improves health during aging, and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size and function. Here we have investigated the role of mitochondrial dynamics during exercise in the genetically tractable model Caenorhabditis elegans. We show that in body wall muscle a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and fitness capacity decline that occur with aging. The plasticity of this mitochondrial dynamics cycle is essential for fitness capacity and its enhancement by exercise training. Surprisingly, among longevity-promoting mechanisms we analyzed, constitutive activation of AMPK uniquely preserves fitness capacity during aging. As with exercise training, this benefit of AMPK is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for fitness capacity to be enhanced by exercise, with our findings together suggesting that exercise enhances muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining fitness capacity and exercise responsiveness during aging, and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion balance, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging. Significance StatementExercise is a powerful anti-aging intervention. In muscle exercise remodels mitochondrial metabolism and connectiveness, but the role of mitochondrial dynamics in exercise responsiveness has remained poorly understood. Working in Caenorhabditis elegans, we find that the mitochondrial dynamics cycle of fission and fusion is critical for fitness capacity, that exercise delays an aging-associated decline in mitochondrial connectiveness and fitness capacity, and that the mitochondrial dynamics cycle is required for the latter benefit. AMPK, which regulates mitochondrial dynamics, is needed for exercise to maintain fitness capacity with age and can recapitulate this exercise benefit. Our data identify the mitochondrial dynamics cycle as an essential mediator of exercise responsiveness, and an entry point for interventions to maintain muscle function during aging.

cell biology↗

bioRxiv2021

Identification of novel therapeutic targets for polyglutamine toxicity disorders that target mitochondrial fragmentation

Huntingtons disease (HD) is one of at least nine polyglutamine toxicity disorders caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine toxicity disorders. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models. In this work, we examine the effect of decreasing mitochondrial fragmentation in a neuronal C. elegans model of polyglutamine toxicity called Neur-67Q. We find that Neur-67Q worms have deficits in mitochondrial morphology in GABAergic neurons and decreased mitochondrial function. Disruption of drp-1 eliminates differences in mitochondrial morphology and rescues deficits in both movement and longevity in Neur-67Q worms. In testing twenty-four RNA interference (RNAi) clones that decrease mitochondrial fragmentation, we identified eleven clones that increase movement and extend lifespan in Neur-67Q worms. Overall, we show that decreasing mitochondrial fragmentation may be an effective approach to treat polyglutamine toxicity disorders and identify multiple novel genetic targets that circumvent the potential negative side effects of disrupting the primary mitochondrial fission gene drp-1. Significance StatementPolyglutamine toxicity disorders are caused by a trinucleotide CAG repeat expansion that leads to neurodegeneration. Both mitochondrial dynamics and function are disrupted in these disorders. In this work we use a simple genetic model organism, the worm C. elegans, to define the role of mitochondrial morphology in polyglutamine toxicity disorders. We show that CAG repeat expansion is sufficient to disrupt mitochondrial morphology and that genetic strategies that decrease mitochondrial fragmentation are beneficial in a neuronal model of polyglutamine toxicity. This work identifies multiple novel genes that are protective in worm models of polyglutamine toxicity, which may serve as potential therapeutic targets for Huntingtons disease and other polyglutamine toxicity disorders.

neuroscience↗

bioRxiv2021

Mitochondrial unfolded protein response transcription factor ATFS-1 increases resistance to exogenous stressors through upregulation of multiple stress response pathways

The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to various insults to the mitochondria through transcriptional changes that restore mitochondrial homeostasis in order to facilitate cell survival. Gene expression changes resulting from the activation of the mitoUPR are mediated by the transcription factor ATFS-1/ATF-5. To further define the mechanisms through which the mitoUPR protects the cell during mitochondrial dysfunction, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause upregulation of genes involved in multiple stress response pathways, including the DAF-16-mediated stress response pathway, the SKN-1-mediated oxidative stress response pathway, the HIF-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Moreover, ATFS-1 is required for the upregulation of stress response genes after exposure to exogenous stressors, especially oxidative stress and bacterial pathogens. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, while disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are upregulated in multiple long-lived mutants, constitutive activation of ATFS-1 in wild-type animals results in decreased lifespan. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stresses through its ability to activate multiple stress response pathways, but that chronic ATFS-1 activation is detrimental for longevity.

genetics↗