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Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways.

ABSTRACT: Mitochondria are dynamic organelles that undergo fusion and fission events. Mitochondrial dynamics are required for mitochondrial viability and for responses to changes in bioenergetic status. Here we describe an insulin-signaling and SCF^LIN-23-regulated pathway that controls mitochondrial fusion in Caenorhabditis elegans by repressing the expression of the mitochondrial proteases SPG-7 and PPGN-1. This pathway is required for mitochondrial fusion in response to physical exertion, and for the associated extension in lifespan. We show that diverse longevity pathways exhibit increased levels of elongated mitochondria. The increased mitochondrial fusion is essential for longevity in the diverse longevity pathways, as inhibiting mitochondrial fusion reduces their lifespans to wild-type levels. Our results suggest that increased mitochondrial fusion is not a major driver of longevity, but rather is essential to allow the survival of older animals beyond their normal lifespan in diverse longevity pathways.Mitochondria can undergo shape changes as a result of fusion and fission events. Here the authors describe how insulin signalling regulates mitochondrial fusion in C. elegans, and show that mitochondrial fusion is necessary, but not sufficient, for longevity of worms with mutations that increase lifespan.

SUBMITTER: Chaudhari SN

PROVIDER: S-EPMC5541002 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways.

Chaudhari Snehal N SN Kipreos Edward T ET

Nature communications 20170803 1

Mitochondria are dynamic organelles that undergo fusion and fission events. Mitochondrial dynamics are required for mitochondrial viability and for responses to changes in bioenergetic status. Here we describe an insulin-signaling and SCF<sup>LIN-23</sup>-regulated pathway that controls mitochondrial fusion in Caenorhabditis elegans by repressing the expression of the mitochondrial proteases SPG-7 and PPGN-1. This pathway is required for mitochondrial fusion in response to physical exertion, and ...[more]

PMID: 28769038

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Project description:The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III of the mitochondrial respiratory chain. Partial loss-of-function mutations in these genes decrease electron transport and greatly increase the longevity of C. elegans by a mechanism that is distinct from that induced by reducing their level of expression by RNAi. Electron transport is a major source of the superoxide anion (O(?) (-)), which in turn generates several types of toxic reactive oxygen species (ROS), and aging is accompanied by increased oxidative stress, which is an imbalance between the generation and detoxification of ROS. These observations have suggested that the longevity of such mitochondrial mutants might result from a reduction in ROS generation, which would be consistent with the mitochondrial oxidative stress theory of aging. It is difficult to measure ROS directly in living animals, and this has held back progress in determining their function in aging. Here we have adapted a technique of flow cytometry to directly measure ROS levels in isolated mitochondria to show that the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants, although overall ROS levels are not, and oxidative stress is low. Furthermore, we show that this elevation is necessary and sufficient to increase longevity, as it is abolished by the antioxidants NAC and vitamin C, and phenocopied by mild treatment with the prooxidant paraquat. Furthermore, the absence of effect of NAC and the additivity of the effect of paraquat on a variety of long- and short-lived mutants suggest that the pathway triggered by mitochondrial superoxide is distinct from previously studied mechanisms, including insulin signaling, dietary restriction, ubiquinone deficiency, the hypoxic response, and hormesis. These findings are not consistent with the mitochondrial oxidative stress theory of aging. Instead they show that increased superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. We propose that superoxide is generated as a protective signal in response to molecular damage sustained during wild-type aging as well. This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response.

Project description:The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the "Myc interaction network" consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.

Dataset Information

Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways.

Publications

Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways.

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