In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way
- PMID: 31285263
- PMCID: PMC6709633
- DOI: 10.1074/jbc.RA119.007601
In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way
Abstract
Patients with fatty liver diseases present altered mitochondrial morphology and impaired metabolic function. Mitochondrial dynamics and related cell function require the uncleaved form of the dynamin-like GTPase OPA1. Stabilization of OPA1 might then confer a protective mechanism against stress-induced tissue damages. To study the putative role of hepatic mitochondrial morphology in a sick liver, we expressed a cleavage-resistant long form of OPA1 (L-OPA1Δ) in the liver of a mouse model with mitochondrial liver dysfunction (i.e. the hepatocyte-specific prohibitin-2 knockout (Hep-Phb2-/-) mice). Liver prohibitin-2 deficiency caused excessive proteolytic cleavage of L-OPA1, mitochondrial fragmentation, and increased apoptosis. These molecular alterations were associated with lipid accumulation, abolished gluconeogenesis, and extensive liver damage. Such liver dysfunction was associated with severe hypoglycemia. In prohibitin-2 knockout mice, expression of L-OPA1Δ by in vivo adenovirus delivery restored the morphology but not the function of mitochondria in hepatocytes. In prohibitin-competent mice, elongation of liver mitochondria by expression of L-OPA1Δ resulted in excessive glucose production associated with increased mitochondrial respiration. In conclusion, mitochondrial dynamics participates in the control of hepatic glucose production.
Keywords: OPA1; gluconeogenesis; hepatocyte; liver; liver metabolism; mitochondria; mitochondrial metabolism; prohibitins.
© 2019 Li et al.
Conflict of interest statement
The authors declare that they have no conflicts of interest with the contents of this article
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Comment in
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Phb1:Phb2 heterodimers in the mitochondria-beyond functional interdependence.J Biol Chem. 2019 Oct 4;294(40):14836. doi: 10.1074/jbc.L119.010788. J Biol Chem. 2019. PMID: 31586026 Free PMC article. No abstract available.
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Reply to Mishra: Prohibitin heterodimers-a complex time dependence for carcinogenesis.J Biol Chem. 2019 Oct 4;294(40):14837. doi: 10.1074/jbc.RL119.010819. J Biol Chem. 2019. PMID: 31586027 Free PMC article. No abstract available.
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