Mitochondrial dynamics are required for the proper regulation of ATP production, mitochondrial survival, and cell function. Alterations of mitochondrial morphology are facilitated by highly conserved fusion and fission proteins. Despite its importance in maintaining cellular function and integrity, the pathways that regulate mitochondrial dynamics have not been fully explored. We have identified a novel pathway for the regulation of mitochondrial fusion. This pathway involves the action of a cullin RING ubiquitin ligase (CRL), that contains the substrate receptor LIN-23. The CRL SCFLIN-23 and its exchange factor CAND-1 promote the activation of the AKT-1 kinase, which inactivates the FOXO transcription factor DAF-16. DAF-16 represses the expression of the mitochondrial proteases SPG-7 and PPGN-1, which inhibit the mitochondrial fusion protein EAT-3. We observed that altering components of this pathway to increase mitochondrial fusion is associated with increased lifespan. We analyzed the mitochondrial morphologies of mutants that exhibit longevity from three distinct mechanisms: daf-2 and age-1, which have extended lifespan from loss of insulin/IGF-like signaling; eat-1 and eat-6, linked to caloric restriction; and glp-1, with lifespan extension resulting from loss of the germline. We discovered that all these diverse long-lived mutants have increased mitochondrial fusion. Further, we observed that mitochondrial fusion contributes to the longevity of these mutants. This indicates that mitochondrial morphology is functionally linked to lifespan extension.
Mitochondria adjust their morphology to coordinate between the cellular demand for energy and the availability of resources. Fused mitochondrial morphology is associated with increased efficiency of ATP production and a reduction in the generation of reactive oxygen species. Conversely, a fragmented morphology is linked to reduced ATP production and mitochondrial uncoupling. Mitochondrial fusion is known to occur in response to physical exertion-induced stress in mice. We show that the same phenomenon occurs in C. elegans and that DAF-16 is required for mitochondrial fusion in response to physical exertion. In daf-16(mu86) mutants, the failure to induce mitochondrial fusion in response to physical exertion is associated with the activation of AMP-activated protein kinase, reflecting a cellular deficit of ATP. Our research has revealed a new pathway for the regulation of mitochondrial fusion, and demonstrated the significance of mitochondrial fusion in physical exertion and longevity. .
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