Dataset Information

InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics

ABSTRACT: Mitochondrial inhibition can confer longevity and health benefits, but excessive bioenergetic impairment triggers severe pathogenesis. This narrow line between benefit and pathology necessitates better understanding of the adaptations that distinguish between these opposing outcomes. The conserved ER calcium channel, InsP3R, represents an underexplored control point for mitochondrial adaptations, as it promotes mitochondrial homeostasis through direct matrix calcium flux and diverse cytosolic pathways. Here we reveal that longevity induced by Complex I inhibition is dependent on InsP3R function, and use C. elegans to dissect the importance of the potentially diverse routes by which intracellular calcium can regulate mitochondrial functions. Although we find the InsP3R potently stimulates mitochondrial bioenergetics; surprisingly, the mitochondrial calcium uniporter is dispensable for respiration and lifespan, indicating InsP3R signaling promotes adaptation independently of ER-to-matrix calcium flux. Instead, we reveal InsP3R signaling promotes adaptive mitochondrial quality control in Complex I mutants by activating actin recruitment and fission-dependent pruning of dysfunctional mitochondria through calmodulin-dependent signaling. Reduced InsP3R function results in maladaptive hyper-expansion of dysfunctional mitochondrial networks and transcriptional dysregulation of mitochondrial biogenesis. Rescuing mitochondrial fission and turnover in InsP3R mutants restores longevity. Overall these findings reveal an inter-organelle calcium signaling pathway essential for controlling mitochondrial scaling during stress while highlighting critical new roles for actin remodeling in mitochondrial longevity paradigms.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE297429 | GEO | 2026/05/31

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Elevated mitochondrial biogenesis and metabolism represent key features of breast cancer stem cells (CSCs), whose propagation is conducive to disease onset and progression. Therefore, interfering with mitochondria biology and function may be regarded as a useful approach to eradicate CSCs. Here, we used the breast cancer cell line MCF7 as a model system to interrogate how mitochondrial fission contributes to the development of mitochondrial dysfunction toward the inhibition of metabolic flux and stemness. We generated an isogenic MCF-7 cell line transduced with Mitochondrial Fission Factor (MCF7-MFF), which is primarily involved in mitochondrial fission. We evaluated the biochemical, molecular and functional properties of MCF7-MFF cells, as compared to control MCF7 cells transduced with the empty vector (MCF7-Control). We observed that MFF over-expression reduces both mitochondrial mass and activity, as evaluated using the mitochondrial probes MitroTracker Red and MitoTracker Orange, respectively. The analysis of metabolic flux using the Seahorse XFe96 revealed the inhibition of OXPHOS and glycolysis in MCF7-MFF cells, suggesting that increased mitochondrial fission may impair the biochemical properties of these organelles. Notably, CSCs activity, assessed by 3D-tumorsphere assays, was reduced in MCF7-MFF cells. A similar trend was observed for the activity of ALDH, a well-established marker of stemness. We conclude that enhanced mitochondrial fission may compromise CSCs propagation, through the impairment of mitochondrial function, possibly leading to a quiescent cell phenotype. Unbiased proteomic analysis revealed that proteins involved in mitochondrial dysfunction, oxidative stress-response, fatty acid metabolism and hypoxia signaling are among the most highly up-regulated in MCF7-MFF cells. Of note, integrated analysis of top regulatory networks obtained from unbiased proteomics in MCF7-MFF cells predicts that this cell phenotype activates signaling systems and effectors involved in the inhibition of cell survival and adhesion, together with the activation of specific breast cancer cell death programs. Overall, our study shows that unbalanced and abnormal activation of mitochondrial fission may drive the impairment of mitochondrial metabolic function, leading to inhibition of CSC propagation, and the activation of quiescence programs. Exploiting the potential of mitochondria to control pivotal events in tumor biology may, therefore, represent a useful tool to prevent disease progression.

Dataset Information

InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets