In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way

Abstract

Edited by Jeffrey E. Pessin 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⌬) 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 cleav-ageofL-OPA1,mitochondrialfragmentation,andincreasedapoptosis. 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⌬ 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⌬ resulted in excessive glucose production associated with increased mitochondrial respiration. In conclusion, mitochondrial dynamics participates in the control of hepatic glucose production. This work was supported by Swiss National Science Foundation Sinergia Grants CRSII3_147637 (to P. M. and J.-C. M.) and 310030_172862 (to M. F.) and by a fellowship from the Fundación Alfonso Martín Escudero (to C. J. S). The authors declare that they have no conflicts of interest with the contents of this article. This article was selected as one of our Editors' Picks. This article contains Tables S1 and S2 and Figs. S1-S8.

Prohibitin 2 deficiency impairs cardiac fatty acid oxidation and causes heart failure

“…Loss of Phb2 in Caenorhabditis elegans and mice leads to embryonic lethality 24,25 . Several tissue specific Phb2 knockout mice have been used to explore its functions in physiological and pathological processes [26][27][28][29] . In forebrainspecific PHB2-deficient mice, tau hyper-phosphorylation and neurodegeneration were observed 29 .…”

“…Deletion of PHB2 in podocytes led to the development of glomerulosclerosis due to PHB2's extramitochondria role in the assembly of the slit diaphragm protein-lipid supercomplex 27 . Hepatocyte-specific Phb2 knockout mice exhibited liver failure and impaired gluconeogenesis 26 . The above studies demonstrate that PHB2 is essential for maintaining normal organ function.…”

Phb1:Phb2 heterodimers in the mitochondria—beyond functional interdependence

“…Li et al (1) showed that in vivo deletion of prohibitin-2 (Phb2) in hepatocytes (Hep-Phb2 Ϫ/Ϫ ) leads to impaired gluconeogenesis, reduced food intake, severe hypoglycemia, and, subsequently, poor survival. Phb2 and its homologous protein Phb1 form heterodimers in the mitochondria and are functionally interdependent (1)(2)(3). Consequently, the knockdown of either member leads to a parallel loss of the other member (1-4).…”

“…Similar to the Hep-Phb2 Ϫ/Ϫ mice, the Hep-Phb1 Ϫ/Ϫ mice display a parallel reduction in the levels of heterodimeric partners in hepatocytes and decreased body weight (1, 4). However, the major liver-specific phenotypes of the Hep-Phb1 Ϫ/Ϫ mice and the Hep-Phb2 Ϫ/Ϫ mice are largely different, with distinctions like increased liver weight and the development of hepatocellular carcinoma in the former and reduced liver weight and severe hypoglycemia in the latter (1,4). Most importantly, the Hep-Phb1 Ϫ/Ϫ mice survive much longer than the Hep-Phb2 Ϫ/Ϫ mice (1, 4) and other, cell type-specific knockout mouse models of Phb2 (2, 3).…”

“…It appears that the mito-chondrial biology of Phb1 and Phb2 is more complex than simple interdependence. The development of the Hep-Phb2 Ϫ/Ϫ mouse model along with the preexisting Hep-Phb1 Ϫ/Ϫ mouse model provided an opportunity to initiate discussion around this stimulating question, which is completely missed by Li et al (1).…”