AAV-mediated Liver-specific MPV17 Expression Restores mtDNA Levels and Prevents Diet-induced Liver Failure

Abstract

Mutations in human MPV17 cause a hepatocerebral form of mitochondrial DNA depletion syndrome (MDS) hallmarked by early-onset liver failure, leading to premature death. Liver transplantation and frequent feeding using slow-release carbohydrates are the only available therapies, although surviving patients eventually develop slowly progressive peripheral and central neuropathy. The physiological role of Mpv17, including its functional link to mitochondrial DNA (mtDNA) maintenance, is still unclear. We show here that Mpv17 is part of a high molecular weight complex of unknown composition, which is essential for mtDNA maintenance in critical tissues, i.e. liver, of a Mpv17 knockout mouse model. On a standard diet, Mpv17-/- mouse shows hardly any symptom of liver dysfunction, but a ketogenic diet (KD) leads these animals to liver cirrhosis and failure. However, when expression of human MPV17 is carried out by adeno-associated virus (AAV)-mediated gene replacement, the Mpv17 knockout mice are able to reconstitute the Mpv17-containing supramolecular complex, restore liver mtDNA copy number and oxidative phosphorylation (OXPHOS) proficiency, and prevent liver failure induced by the KD. These results open new therapeutic perspectives for the treatment of MPV17-related liver-specific MDS.

The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential

“…Remarkably, these mice showed signs of premature aging: gray coat color early in adulthood, age-dependent glomerulosclerosis, sensorineural deafness (6 -9), and cataract. 5 The recent findings where liver-specific expression of human MPV17 in Mpv17 Ϫ/Ϫ mice restored mtDNA copy number and oxidative phosphorylation proficiency and prevented ketogenic diet-induced liver failure (10) underscore the link between MPV17 function and MPV17-related MDDS.…”

Emerging concepts in the therapy of mitochondrial disease

“…Similar to the human disease, the mouse model shows profound decrease of mtDNA copy number in the liver, but, in contrast to humans, hardly any clinical phenotype of hepatopathy is detected in standard conditions [103]. However, liver steatosis evolving into cirrhosis associated with fatal liver failure is produced in Mpv17 −/− exposed to KD [87]. We showed that an AAV2/8 viral vector expressing human MPV17 wt fully rescued the mtDNA depletion and prevented the KD-induced cirrhosis in Mpv17 −/− mice, when the treatment was initiated before starting the KD regime, whereas the same treatment significantly delayed but not arrested disease progression when initiated after starting KD [87].…”

“…In a preclinical trial on the deletor mouse, KD slowed the progression of mitochondrial myopathy [85]. However, other reports showed that KD can have the opposite effect, and worsens the mitochondrial defect in vivo, for instance in the Mterf2 −/− [86], or the Mpv17 -/− mouse models [87].…”

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders

“…Recently, several groups reported efficient and specific targeting of the liver using systemic application of liver-specific AAV2/8 vectors (Bottani et al, 2014;Di Meo et al, 2012;Torres-Torronteras et al, 2014). Gene expression was restricted to the liver by using liver specific promoters.…”