Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Abstract

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies. Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease.

Figure 1

Superoxide production and reactive nitrogen species reactions in mitochondria. During electron transfer superoxide (O₂^●–) is generated within Complexes I (b, c) and III (a) due to the presence of stable semiquionine anion species. Solid arrows illustrate forward electron flow, whereas dashed arrows indicate reverse electron flow through Complex II to increase O₂^●– production in ComplexI(c). O₂^●– dismutation to hydrogen peroxide (H₂O₂) by manganese superoxide dismutase (MnSOD) affects cellular redox signaling pathways (d). Increased iNOS expression leads to diffusion of nitric oxide (NO) into mitochondria where it inhibits cytochrome c oxidase (e), which increases O₂^●– generation.

Figure 2

Overlapping alterations to the liver mitochondrial proteome contribute to the development of alcohol-induced liver disease. This figure illustrates the concept that there is a unique mitochondrial sub-proteome that when altered by chronic alcohol mediated mtDNA/ribosome damage, increased ROS/RNS production, and energy deficits contribute to the development of alcohol hepatotoxicity. These alterations involve changes in both protein levels (panel A) and post-translational modifications (PTMs, panel B) to this susceptible population of mitochondrial proteins.