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Mitochondrial Apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways

ABSTRACT: A variety of metabolic disorders are aggravated by obesity. Since mitochondria play key roles in various catabolic and anabolic reactions encompassing lipid metabolism, optimal functioning of mitochondria is critical in preventing various pathologies. Increased amounts of the apolipoprotein O /MIC26 were found in diabetic patients along with lipid accumulation in murine liver upon MIC26 expression. MIC26 is a MICOS complex constituent present in the mitochondrial inner membrane. The functional interplay between MIC26 and cellular metabolome is not understood. Therefore, we employed a multi-omics approach in WT and MIC26 knockout HepG2 cellular models in normoglycemic and hyperglycemic conditions, along with a variety of functional assays. We found that MIC26 is necessary for maintaining glycolysis and lipid metabolism via CPT1A along with cholesterol synthesis in a nutrient-dependent manner. MIC26 deletion led to metabolic rewiring of glutamine utilisation leading us to propose that mitochondrial ultrastructure and cellular metabolome are functionally interdependent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248848 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that associate with Argonaute 2 protein to regulate gene expression at the post-transcriptional level in the cytoplasm. However, recent studies have reported that some miRNAs localize to and function in other cellular compartments. Mitochondria harbour their own genetic system that may be a potential site for miRNA-mediated post-transcriptional regulation. We aimed at investigating whether nuclear-encoded miRNAs can localize to and function in human mitochondria. To enable identification of mitochondrial-enriched miRNAs, we profiled the mitochondrial and cytosolic RNA fractions from the same HeLa cells by miRNA microarray analysis. Mitochondria were purified using a combination of cell fractionation and immunoisolation, and assessed for the lack of protein and RNA contaminants. We found 57 miRNAs differentially expressed in HeLa mitochondria and cytosol. Of these 57, a signature of 13 nuclear-encoded miRNAs was reproducibly enriched in mitochondrial RNA and validated by RT-PCR for hsa-miR-494, hsa-miR-1275 and hsa-miR-1974. This study provides the first comprehensive view of the localization of RNA interference components to the mitochondria. Our data outline the molecular bases for a novel layer of crosstalk between nucleus and mitochondria through a specific subset of human miRNAs that we termed ‘mitomiRs’. To assess whether nuclear-encoded miRNA are detectable in human mitochondria, we performed the following four steps approach. First, cultured HeLa cells were allowed to reach 80-100% confluence and subjected to fractionation in order to isolate the cytosolic fraction. From the same HeLa cells, mitochondria were isolated by immunomagnetic Anti-TOM22 MicroBeads from the Mitochondria Isolation Kit (Miltenyi Biotec). In total, six mitochondria preparations were perfromed, three of these were additionally treated with RNase A. Second, total RNA was extracted from the mitochondrial and cytosolic fractions. Third, mitochondrial and cytosolic RNA were respectively profiled by microRNA microarray analysis. Last, data were analyzed and normalized.Three independent assays were performed.

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Mitochondrial Apolipoprotein MIC26 is a metabolic rheostat regulating central cellular fuel pathways

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