Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 34, Pages 12581-12598Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.007601
Keywords
liver metabolism; mitochondria; hepatocyte; gluconeogenesis; mitochondrial metabolism; OPA1; prohibitins; liver
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Funding
- Swiss National Science Foundation Sinergia [CRSII3_147637, 310030_172862]
- Fundacion Alfonso Martin Escudero
- Swiss National Science Foundation (SNF) [CRSII3_147637, 310030_172862] Funding Source: Swiss National Science Foundation (SNF)
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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-OPA1 Delta) 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-OPA1 Delta 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-OPA1 Delta resulted in excessive glucose production associated with increased mitochondrial respiration. In conclusion, mitochondrial dynamics participates in the control of hepatic glucose production.
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