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Grupa Twój Zdrowy Ruch

Publiczna·4 uczestników
Joseph Bennett
Joseph Bennett

Mitochondria And Longevity

Next steps for the researchers including testing the role mitochondrial networks have in the effect of fasting in mammals, and whether defects in mitochondrial flexibility might explain the association between obesity and increased risk for age-related diseases.

Mitochondria and longevity


The team also studied human cell lines that featured a mutation called 3243 MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome), of which one hallmark is mutated mitochondria. The higher the percentage of mutated mitochondria, the lower the amount of humanin, Yen said, which suggests that low humanin could be a marker of mitochondrial dysfunction in general.

The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity.

Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in Caenorhabditis elegans by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR. We found that clk-1, isp-1, and nuo-6 worms all exhibit an ATFS-1-dependent activation of the mitoUPR. While loss of atfs-1 during adulthood does not affect lifespan in any of these strains, absence of atfs-1 during development prevents clk-1 and isp-1 worms from reaching adulthood and reduces the lifespan of nuo-6 mutants. Examining the mechanism by which deletion of atfs-1 reverts nuo-6 lifespan to wild-type, we find that many of the transcriptional changes present in nuo-6 worms are mediated by ATFS-1. Genes exhibiting an ATFS-1-dependent upregulation in nuo-6 worms are enriched for transcripts that function in stress response and metabolism. Consistent, with this finding, loss of atfs-1 abolishes the enhanced stress resistance observed in nuo-6 mutants and prevents upregulation of multiple stress response pathways including the HIF-1-mediated hypoxia response, SKN-1-mediated oxidative stress response and DAF-16-mediated stress response.

Our results suggest that in the long-lived mitochondrial mutant nuo-6 activation of the mitoUPR causes atfs-1-dependent changes in the expression of genes involved in stress response and metabolism, which contributes to the extended longevity observed in this mutant. This work demonstrates that the mitoUPR can modulate multiple stress response pathways and suggests that it is crucial for the development and lifespan of long-lived mitochondrial mutants.

The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that enables the mitochondria to communicate with the nucleus to upregulate mitochondrial chaperones and alter metabolism in response to mitochondrial stresses [1, 2]. This response is controlled by ATFS-1 (activating transcription factor associated with stress-1) in Caenorhabditis elegans [3] and ATF5 in mammals [4]. The ATFS-1 protein has both a mitochondria targeting sequence and a nuclear localization signal. Under normal conditions, ATFS-1 is imported into the mitochondria and degraded by the Lon protease [3]. When the mitochondria is stressed (e.g., by exposure to ROS [5], disrupted stoichiometry of the subunits of the electron transport chain [2], or mutations affecting mitochondria function [6]), the import of ATFS-1 into the mitochondria is prevented, allowing ATFS-1 to travel to the nucleus where it upregulates the expression of mitochondrial chaperones, various detoxification enzymes and metabolic enzymes [7].

In addition to ATFS-1, there are multiple other proteins involved in the mitoUPR including the mitochondrial matrix protease ClpP, the mitochondrial matrix peptide exporter HAF-1, the small ubiquitin-like protein, UBL-5, and the transcription factor DVE-1 [8,9,10]. Under conditions of mitochondrial stress, ClpP cleaves mitochondrial proteins, which are exported by HAF-1. These peptides have been proposed to inhibit the mitochondrial import of ATFS-1 [7], which accumulates in the cytoplasm and then travels to the nucleus where it acts in a complex with UBL-5 and DVE-1 to mediate the transcriptional changes associated with the mitoUPR. Among other changes, this includes increased expression of mitochondrial chaperone proteins, such as HSP-6, that help to re-establish proteostasis in the mitochondria.

Based on the observation that the mitoUPR is activated by knockdown of cytochrome c oxidase-1 (CCO-1) [2] and the fact that RNAi against cco-1 increases lifespan [11], a role for the mitoUPR in longevity was explored by knocking down the expression of required components of the mitoUPR in long-lived worms with mildly impaired mitochondrial function. It was found that knocking down the expression of ubl-5 reduces the lifespan of two long-lived mitochondrial mutants called clk-1 and isp-1, but does not affect the lifespan of wild-type worms [12]. Similarly, decreasing the expression of dve-1 reduced isp-1 lifespan, but also markedly decreased wild-type lifespan making this observation more difficult to interpret [12]. It was subsequently shown that knocking down the expression of the mitochondrial ribosomal protein S5 (mrps-5), which causes an imbalance in between nuclear- and mitochondrially encoded components of the electron transport chain, causes both the activation of the mitoUPR and increased lifespan [13]. Importantly, decreasing ubl-5 levels with RNAi reduced the increase in lifespan caused by mrps-5 knockdown [13]. Activation of the mitoUPR has also been implicated in the lifespan extension caused by different types of bacteria [14] possibly through elevated reactive oxygen species [15]. Combined, these studies suggested that the mitoUPR plays a role in specific longevity pathways.

However, a subsequent study has suggested that the relationship between the mitoUPR and longevity is more complicated. After completing an RNAi screen for genes that activate the mitoUPR, it was shown that only some of these genes increase lifespan, while others decrease it [16]. This indicates that activation of the mitoUPR is not sufficient to increase lifespan. It was also shown that RNAi against cco-1 can still increase the lifespan of an atfs-1 deletion mutant (tm4525) even though the atfs-1 mutation prevented the activation of the mitoUPR (as measured with an hsp-6 reporter strain) [16]. Similarly, RNAi against atfs-1 prevented the activation of the mitoUPR in isp-1 mutants but did not impact longevity. Combined, these results suggest that activation of the mitoUPR is not required for longevity that is induced by cco-1 RNAi or isp-1 mutation. Similarly, it was shown that the increase in lifespan resulting from RNAi against a putative cytochrome c oxidase (F29C4.2) was not affected by loss of atfs-1 [17]. Thus, at present, the role of the mitoUPR in determining longevity remains unclear [18].

In this work, we explore the role of the mitoUPR in the lifespan of three long-lived mitochondrial mutants: clk-1, isp-1, and nuo-6 [19,20,21,22]. These genes encode proteins involved in the mitochondrial electron transport chain including a hydroxylase required for the synthesis of ubiquinone, a subunit of complex III called the Rieske iron sulfur protein and a subunit of complex I, respectively. In clk-1 and isp-1 mutants, we find that the mitoUPR is not required during adulthood for their long lifespans, but is required for these worms to develop to adulthood, making it impossible to assess its contributions to longevity conclusively. Importantly, nuo-6 worms do not require the mitoUPR to develop to adulthood, thereby providing the opportunity to assess the role of the mitoUPR in longevity. We find that in nuo-6 worms the activation of the mitoUPR causes the upregulation of stress response genes and metabolic enzymes and that this results in increased resistance to multiple stresses and long lifespan.

In order to examine the role of the mitoUPR in the long lifespan of the mitochondrial mutants clk-1, isp-1, and nuo-6, we first sought to confirm that the mitoUPR is upregulated in these mutants [6, 12, 23]. To do this, we crossed the mitochondrial mutant strains to a reporter strain for the mitoUPR target gene hsp-6 (Phsp-6::GFP) [2]. We found that clk-1, isp-1, and nuo-6 worms all exhibit increased fluorescence compared to wild-type worms (Fig. 1a) indicating activation of the mitoUPR. We found that fluorescence from the mitoUPR reporter remained significantly increased until day 5 of adulthood (Fig. 1b). Since GFP-tagged proteins can have a half-life of multiple days, it is possible that fluorescence from the mitoUPR reporter strain during adulthood resulted from mitoUPR activity during development. To confirm that the mitoUPR remains activated in adulthood, we examined RNAseq data from clk-1, isp-1, and nuo-6 mutants at the young adult stage [24]. We found that hsp-6 mRNA is significantly increased in all three strains and is correlated with atfs-1 mRNA levels (Additional file 1: Figure S1).

To elucidate the role of the mitoUPR in the long-lifespan of clk-1, isp-1, and nuo-6 worms, we examined how decreasing atfs-1 expression affected their longevity. We used three different paradigms of increasing severity: atfs-1 RNAi beginning in the experimental L4 generation, atfs-1 RNAi beginning in the parental L4 generation and an atfs-1(gk3094) deletion mutation.

Finally, we examined the effect of an atfs-1 deletion mutation on the lifespan of the mitochondrial mutants. We found that clk-1;atfs-1 double mutants produce few progeny and that the progeny arrest at the L1 or L2 stage of development (Fig. 2i). Similarly, we found that isp-1;atfs-1 double mutants arrest at the L2 or L3 stage (Fig. 2j). In contrast, nuo-6;atfs-1 double mutants were found to be viable and fertile. Examining the lifespan of these double mutants revealed that the atfs-1 deletion completely reverted nuo-6 lifespan to wild-type but did not impact wild-type lifespan (Fig. 2k). The atfs-1 deletion reduced expression of atfs-1 and hsp-6 and increased the expression of hsp-16.11 and hsp-16.2 (Fig. 2l). Combined, these results demonstrate that atfs-1 is required for the development of clk-1 and isp-1 worms to adulthood and for the longevity of nuo-6 worms. Loss of atfs-1 does not decrease wild-type lifespan, and in the mitochondrial mutants, atfs-1 is not needed during adulthood for normal lifespan. 041b061a72

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