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Increase in ER-mitochondria contacts and mitochondrial fusion are hallmarks of mitochondrial activation during embryogenesis

ABSTRACT: Mitochondrial energy production is essential for development, yet the mechanisms underlying the continuous increase in mitochondrial activity during embryogenesis remain elusive. Using zebrafish as a model system for vertebrate development, we identify two sequentially acting mechanisms that could contribute to the rise in mitochondrial activity: an increased association between mitochondria and the endoplasmic reticulum (ER) at early stages, followed by the fusion of mitochondria leading to their elongated morphology at later embryonic stages. By comprehensively profiling mitochondrial activity, abundance, morphology, metabolome, proteome and phospho-proteome as well as respiratory chain enzymatic activity, we find that the increase in mitochondrial activity during embryogenesis does not require mitochondrial biogenesis, is not limited by metabolic substrates at early stages, and occurs under steady levels of respiratory chain complexes and enzymatic activities. Instead, our analyses pinpoint a previously unexplored increase in mitochondrial-ER association during early stages in combination with changes in mitochondrial morphology at later stages as possible contributors to the rise in mitochondrial activity during embryogenesis. Overall, our systematic profiling of the molecular and morphological changes to mitochondria during embryogenesis provides a valuable resource for further studying mitochondrial function during embryogenesis.

ORGANISM(S): Danio rerio

PROVIDER: GSE267318 | GEO | 2024/05/16

REPOSITORIES: GEO

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Project description:Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. While the role of ubiquitin (Ub) ligase PARKIN in mitophagy has been extensively studied, increasing evidence suggests the existence of PARKIN-independent mitophagy in highly metabolically active organs such as the heart. Here, we identify a crucial role for Cullin-RING Ub ligase 5 (CRL5) in basal mitochondrial turnover in cardiomyocytes. CRL5 is a multi-subunit Ub ligase comprised by the catalytic RING box protein RBX2 (also known as SAG), scaffold protein Cullin 5 (CUL5), and a substrate-recognizing receptor. Analysis of the mitochondrial outer membrane-interacting proteome uncovered a robust association of CRLs with mitochondria. Subcellular fractionation, immunostaining, and immunogold electron microscopy established that RBX2 and Cul5, two core components of CRL5, localizes to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, and increased cell death in cardiomyocytes. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. Notably, the action of RBX2 in mitochondria is not dependent on PARKIN, and PARKIN gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria. Proteomics and biochemical analyses further revealed a global impact of RBX2 deficiency on the mitochondrial proteome and identified several mitochondrial proteins as its putative substrates. These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that controls mitophagy under physiological conditions in a PARKIN-independent, PINK1-dependent manner, thereby regulating cardiac homeostasis.

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Increase in ER-mitochondria contacts and mitochondrial fusion are hallmarks of mitochondrial activation during embryogenesis

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