[
International Worm Meeting,
2021]
Mitochondria are important regulators of healthspan and lifespan, and their perturbation has been correlated with various pathological conditions. Mitochondrial abundance and function are controlled by the opposing processes of mitochondrial biogenesis and mitophagy. While the mechanisms underlying mitophagy have been extensively studied, mitochondrial biogenesis is not well understood. We find that the mRNA decapping and the CCR-4/NOT complexes physically associate with mitochondria and oppositely regulate mitochondrial abundance during ageing. Components of the two complexes tightly control the fate of specific nuclear encoded mitochondrial transcripts, including those for ETC components and mitochondrial biogenesis regulators. Our findings indicate that post-transcriptional regulation of select mitochondrial transcripts modulates mitochondrial abundance and function, as well as, lifespan and stress resistance in C. elegans. The tight evolutionary conservation of the decapping and the CCR-4/NOT complex components suggests that similar mechanisms contribute to mitochondrial homeostasis during ageing across diverse organisms.
[
International Worm Meeting,
2021]
Oxygen deprivation, referred to as hypoxia, entails extensive reprogramming of intracellular energy metabolism. For example, reduction of mitochondrial respiration and enhancement of glycolytic metabolism are commonly observed in hypoxic cells. These adaptations are mainly orchestrated by the hypoxia-inducible factor 1 (HIF-1). Interestingly, recent studies have shown that mitochondrial respiration is necessary for tumor growth under hypoxic conditions. However, the molecular mechanisms that adjust mitochondrial function upon oxygen deprivation remain elusive. We find that, while impairment of mitochondrial oxidative phosphorylation (OXPHOS) triggers HIF-1 activation, this is not sufficient for survival under oxygen limitation. By contrast, both mitochondrial OXPHOS and glycolysis are required for hypoxia resistance. To gain further insight into hypoxia resistance mechanisms, we conducted a genetic screen for mitochondrial genes involved in HIF-1-independent survival under hypoxia. We found that the mitochondrial phospholipid trafficking mediator MDMH-35 and its interacting partners B0334.4 (PRELID-1) and F15D3.6 (PRELID-3), contribute to preserve mitochondrial function and confer resistance to hypoxic stress. In addition, we show that PRELID-1 and PRELID-3 antagonistically regulate mitochondrial phosphatidylserine (PS) trafficking and phosphatidylethanolamine (PE) synthesis. Together these findings indicate that balancing mitochondrial phospholipid content is necessary for survival under hypoxia, independently of HIF-1.
Klapa, Maria I., Daskalaki, Ioanna, Tavernarakis, Nektarios, Lionaki, Eirini, Gkikas, Ilias, Ioannidi, Maria-Konstantina
[
International Worm Meeting,
2021]
Sustained mitochondrial fitness is intimately linked to healthy aging and longevity while it relies on coordinated mitochondrial biogenesis, maintenance, and clearance. These processes are fine-tuned by the constant targeting of proteins into the organelle. Mitochondrial protein import is a complex procedure mediated by conserved protein translocases in the outer and inner mitochondrial membranes. We are investigating how modulation of mitochondrial protein import translocases affects mitochondrial abundance, morphology, and function, ultimately impacting organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, triggers a discrete longevity paradigm. MitoMISS longevity depends on ATFS-1, the transcription factor driving mitochondrial unfolded protein response. However, mitochondrial chaperones are not causatively linked to longevity. Mechanistically, we show that MitoMISS initiates an ATFS-1-dependent unconventional UPRmt, leading to metabolic rewiring. Metabolic profiling of MitoMISS animals points to an adaptive metabolic response, encompassing fat mobilization, glycolysis and de novo serine biosynthesis. Genetic epistasis indicates that both glycolysis and de novo serine biosynthesis are prerequisites for MitoMISS associated longevity. Our findings extent the pro-longevity role of UPRmt and reveal a homeostatic mechanism that engages ATFS-1 to coordinate an adaptive metabolic shift that drives lifespan extension.