Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

Abstract

Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.

Neuronal Cell Death and Degeneration through Increased Nitroxidative Stress and Tau Phosphorylation in HIV-1 Transgenic Rats

“…Although we have not evaluated the role of activated p-p38K in tau-phosphorylation in our study, it is likely that its role could be as similar as that of p-JNK. Therefore, suppression of activated p-JNK (and/or p-p38K) can be an excellent target for preventing or treating various neurodegenerative diseases, as recently reviewed [40, 82]. …”

Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: Role of disturbed lipid homeostasis and increased oxidative stress

“…However, CYP2E1 levels were actually decreased in response to HFRD in our model, although its levels were shown to be increased by experimental models of NAFLD and patients (Aljomah et al, 2015). Inducible nitric oxide synthase (iNOS) (Saha and Pahan, 2006), which is known to produce greater amounts of nitric oxide (NO) than other NOS isoforms (Akbar et al, 2016), has also been reported to play a critical role in the development and/or progression of alcoholic fatty liver disease (AFLD) and NAFLD (Abdelmegeed and Song, 2014), since iNOS-null mice are resistant to AFLD (McKim et al, 2003) and NAFLD (Nozaki et al, 2015). In addition, iNOS was reported to play an important role in the onset of hepatic steatosis and inflammation in response to chronic exposure to 30% fructose solution in drinking water (Spruss et al, 2011).…”

Cytochrome P450-2E1 is involved in aging-related kidney damage in mice through increased nitroxidative stress

“…Furthermore, our previous reports showed causal roles of mitochondrial dysfunction in promoting full-blown tissue injury usually observed at later time points following exposure to CYP2E1 substrates such as APAP (Abdelmegeed et al, 2013; Abdelmegeed et al, 2010) and carbon tetrachloride (Jang et al, 2015) or under pathological conditions (Moon et al, 2006; Moon et al, 2008). The potential role of mitochondria in mediating the aging-related renal damage in WT mice warrant further investigation with treatment agents targeting mitochondria, such as antioxidant mito-Q (Akbar et al, 2016; Song et al, 2014), to establish their importance in the aging process and disease manifestation. Interestingly, despite the fact that mitochondrial respiration is essential for the production of ATP and that oxidatively-damaged mitochondria may produce less amounts of ATP, in our study, the levels of ATP in aged mice were not significantly changed, suggesting an adaptive mechanism (Anantharaju et al, 2002; Abdelmegeed et al, 2016).…”