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Mitochondrial networking in times of integrated stress

July 28, 2020 @ 12:00 pm - 1:00 pm UTC-5

AJ Hinton flyer

Defective mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) have been associated with insulin Resistant Type 2 Diabetes Mellitus (T2D). MERCs are enriched with specific proteins and lipids that are believed to mediate inter-organellar communication. Previously, we demonstrated that OPA-1 deficiency in skeletal muscle induces ER stress, which correlated with the upregulation of Mitofusin-2 (MFN-2), which is a known tethering protein in MERCs. Therefore, we hypothesized that OPA1-induced mitochondrial stress results in the narrowing of MERC distance through tethering proteins’ upregulation. To test this hypothesis, we surveyed several MERCs proteins in OPA1-deficient Drosophila muscle, mouse muscle, and primary myotubes. Ablation of OPA-1 in all three models increased MERC proteins (MFN-2, PACS-2, GRP75, BIP, and IP3R3) and ER stress proteins (ATF4, ATF6, BIP, CHOP). Analysis of proximity ligation assay revealed that VDAC and IP3R3 and MFN-1 and MFN-2 interactions were increased in OPA-1 deficient skeletal muscle. SBF-SEM and TEM Analysis of OPA-1 deficient in all three models confirmed an increase in the number of MERCs and a reduced MERC distance. TUDAC treatment decreased ER stress Gene Expression (ATF4 and CHOP) and MERC gene expression (IP3R3, GRP75, VDAC3, MFN-2) in OPA-1 deficient skeletal muscle compared to control. Promoter analysis of a CHIPseq data set revealed that ATF4 binds to the promoters of MERCs that are upregulated in OPA-1 deficient samples. Collectively, these data suggest that loss of OPA-1 in muscle cells results in the induction of MERC proteins, which correlates with increased MERCS formation. These findings may represent a compensatory mechanism in response to mitochondrial stress that is precipitated by OPA1 deficiency.


July 28, 2020
12:00 pm - 1:00 pm UTC-5
Event Category:




Quantitative Systems Biology Center

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