Mitochondrial Dysfunction in Lyssavirus-Induced Apoptosis

Abstract

Lyssaviruses are highly neurotropic viruses associated with neuronal apoptosis. Previous observations have indicated that the matrix proteins (M) of some lyssaviruses induce strong neuronal apoptosis. However, the molecular mechanism(s) involved in this phenomenon is still unknown. We show that for Mokola virus (MOK), a lyssavirus of low pathogenicity, the M (M-MOK) targets mitochondria, disrupts the mitochondrial morphology, and induces apoptosis. Our analysis of truncated M-MOK mutants suggests that the information required for efficient mitochondrial targeting and dysfunction, as well as caspase-9 activation and apoptosis, is held between residues 46 and 110 of M-MOK. We used a yeast two-hybrid approach, a coimmunoprecipitation assay, and confocal microscopy to demonstrate that M-MOK physically associates with the subunit I of the cytochrome c (cyt-c) oxidase (CcO) of the mitochondrial respiratory chain; this is in contrast to the M of the highly pathogenic Thailand lyssavirus (M-THA). M-MOK expression induces a significant decrease in CcO activity, which is not the case with M-THA. M-MOK mutations (K77R and N81E) resulting in a similar sequence to M-THA at positions 77 and 81 annul cyt-c release and apoptosis and restore CcO activity. As expected, the reverse mutations, R77K and E81N, introduced in M-THA induce a phenotype similar to that due to M-MOK. These features indicate a novel mechanism for energy depletion during lyssavirus-induced apoptosis.

Chandipura Virus Induces Neuronal Death through Fas-Mediated Extrinsic Apoptotic Pathway

“…In both cases, we found a highly significant rise in caspase-3 activity at 12 hpi (P Ͻ 0.01). In order to prove that caspase-3 plays a pivotal role in CHPV-mediated neurodegeneration, it was knocked down using esiCaspase-3 (endoribonuclease-prepared siRNA) in Neuro2A cells (34). It was observed that there is a significant downregulation in cleaved caspase-3 and its downstream molecule cleaved PARP in immunoblot analysis at 12 hpi (Fig.…”

“…Viruses are obligatory intracellular parasites, and they modulate the host's intracellular machinery in their favor to prolong their survival (34)(35)(36). An important armory in their arsenal is modu- lation of apoptosis in order to complete their replicative cycle and kill the host when it requires releasing its matured replicates for further invasion (37)(38)(39)(40).…”

Intergenotypic Replacement of Lyssavirus Matrix Proteins Demonstrates the Role of Lyssavirus M Proteins in Intracellular Virus Accumulation

“…M is essential for virus assembly and release (32) and is able to support virus budding even in the absence of G (31). In addition, RABV M regulates viral RNA synthesis (14,17) and has been described to contribute to TRAIL-dependent induction of apoptosis (25) and to mitochondrial dysfunction (18). Recently, the X-ray crystal structure analysis of M of genotype 2 Lagos bat lyssavirus demonstrated a high conservation of M structures within the rhabdovirus family, despite the lack of sequence conservation between the lyssavirus and vesiculovirus genera (19).…”

Protein X of Borna Disease Virus Inhibits Apoptosis and Promotes Viral Persistence in the Central Nervous Systems of Newborn-Infected Rats

“…The nonstructural protein 3A of hepatitis C virus accumulates on mitochondria, rendering the cells sensitive to apoptosis (35). The matrix protein of Mokola virus, a low-pathogenicity lyssavirus, promotes apoptosis by targeting subunit 1 of the cytochrome c oxidase of the mitochondrial respiratory chain (14). The small PB1-F2 protein of influenza A virus and the viral protein R (Vpr) of human immunodeficiency virus type 1 promote apoptosis by interaction with the adenine nucleotide translocator and the voltage-dependent anion channel 1 components of the permeability transition pore (PTP) complex and significantly contribute to the pathogenic potential of these viruses (6,25,54).…”