Targeting Endoplasmic Reticulum and/or Mitochondrial Ca2+ Fluxes as Therapeutic Strategy for HCV Infection

Abstract

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Viroporins and inflammasomes: A key to understand virus-induced inflammation

“…Following virus uptake in macrophages, HCV proteins are transiently produced but then decay. HCV proteins have been shown to stimulate ROS accumulation and regulate ion efflux [109,112,113].…”

Role of Mitochondria in Viral Infections

“…Hepatitis C virus (HCV) is a positive-strand RNA virus of family Flaviviridae. During infection, HCV proteins localize to mitochondrial membranes, induce ER stress and cause depletion of ER calcium stores, leading to mitochondrial dysfunction [ 123 , 124 ]. The non-structural protein 5A (NS5A) of HCV inhibits electron transport chain enzyme complex I activity to promote mitochondrial calcium uptake, mitochondrial permeability transition, and ROS production [ 17 , 125 ].…”

Therapeutic implications of novel peptides targeting ER–mitochondria Ca2+-flux systems

“…Although CsA itself showed controversial results in clinical trials for cardioprotection [153][154][155], these improved versions of CsA have yet to be clinically tested for this therapeutic application. Interestingly, NIM-811 (SDZ 811) and Debio-025 (alisporivir) also appear to significantly reduce hepatitis C virus (HCV) replication and prevent HCV-induced mitochondrial Ca 2+ overload; the latter being a molecular event recently identified as seminal in HCV-infected hepatocytes [151,156]. Although both CsA-derived peptides had already been clinically tested as relatively safe HCV treatments [157,158] (registration number NCT01446250, NCT00983060), they have so far been approved solely for investigational purposes.…”