Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

Abstract

Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury.

Graphical abstract

Fig. 1

Five major types of PTM contributing to mitochondrial dysfunction and tissue injury in AFLD, NAFLD and acute liver damage. Alcohol, smoking, high fat diet, hepatotoxic compounds and aberrant genetic mutations can lead to increased production of ROS and RNS either individually or synergistically, leading to elevated nitroxidative stress. Under increased nitroxidative stress, many cellular (mitochondrial) proteins can be modified by different forms of PTM and inactivated, leading to mitochondrial dysfunction. Under increased mitochondrial dysfunction, greater amounts of ROS/RNS are produced while energy supply and normal metabolism can be suppressed. Accumulation of fat resulting from disrupted fat oxidation can trigger insulin resistance and lipotoxicity while protein adducts can stimulate immune responses. Sustained mitochondrial dysfunction would lead to the development of vicious cycles of PTMs and energy depletion and lipotoxicity, ultimately promoting tissue injury (necrosis/apoptosis). Many small molecule antioxidants contained in fruits and vegetables as well as exercise and calorie restrictions can be used to prevent or reduce the nitroxidative stress. Uni-directional and bi-directional arrows indicate exclusive and mutual influences (in vicious cycles), respectively.

Fig. 2

Multiple PTM of ALDH2 protein, contributing to its inactivation. Different types of PTM on ALDH2 are illustrated. Most PTMs led to the suppression of ALDH2 activity, although phosphorylation of ALDH2 by the PKCε isoform was shown to stimulate the ALDH2 activity, as recently reviewed . The suppressed activities of ALDH2 and other isozymes, all of which share the 100%-conserved active site Cys residue, likely contribute to increased levels of toxic and carcinogenic acetaldehyde (AcAH) and lipid peroxides (MDA and 4-HNE) following exposure to ethanol, high fat and other toxic compounds. ER stress, mitochondrial dysfunction and tissue injury can be observed in acute and sub-chronic cases. Long-term chronic suppression of ALDH2 and other isozymes can also contribute to fibrosis, cirrhosis and carcinogenesis. The negative sign represents the inactivation of ALDH2 and other isozymes.

Fig. 3

Overlapping PTMs between AFLD and NAFLD. Overlapping PTMs commonly observed in both AFLD and NAFLD are illustrated. However, acetaldehyde–protein adduct (AA–adduct) , , NEL-adduct , AA-AGE-adduct , and hydroxyethyl-adduct , seem uniquely observed in AFLD. These PTMs observed in AFLD and NAFLD are likely to suppress the functions of the target proteins, contributing to altered cell signaling, ER stress, mitochondrial dysfunction, fat accumulation and inflammatory tissue injury.