Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies

Abstract

Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver), neurologic and psychiatric, autoimmune, and dermatologic disorders. The mechanistic grounds for mitochondrial dysfunction (MDF) along with the occurrence of oxidative stress (OS) have been investigated within the pathogenesis of individual disorders or in groups of interrelated disorders. We attempt to review broad-ranging pathologies that involve mitochondrial-specific deficiencies or rely on cytosol-derived prooxidant states or on autoimmune-induced mitochondrial damage. The established knowledge in these subjects warrants studies aimed at elucidating several open questions that are highlighted in the present review. The relevance of OS and MDF in different pathologies may establish the grounds for chemoprevention trials aimed at compensating OS/MDF by means of antioxidants and mitochondrial nutrients.

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…We have been most intrigued with therapeutic avenues that focus on mitochondrial involvement in the etiology of the disease [Tillement et al, 2011;Breuer et al, 2012;Chung et al, 2012;Manji et al, 2012;Milone, 2012;Schapira, 2012;Swerdlow, 2012;Breuer et al, 2013;Selfridge et al, 2013;Pagano et al, 2014;Swerdlow et al, 2014;Gody n et al, 2016], and a number of mitochondria-targeted small molecules, such as dimebon [Moreira et al, 2010], MitoQ [Su et al, 2010;Carvalho et al, 2012;Reddy et al, 2012], and lipoic acid derivatives [Bolaños et al, 2009;Rosini et al, 2011;Mecocci and Polidori, 2012;Anand et al, 2014], have reached various stages of clinical trials. However, the results to date with these first-generation synthetic compounds have not been encouraging [Miller, 2010;Galasko et al, 2012;Danta and Piplani, 2014] and their mechanisms of action, target access engagement, and other pharmaceutical properties have not always been clear.…”

“…Patients presenting with neurological disorders, for example, AD, PD, and Gulf War Illness (GWI), are burdened with a significant number of dysfunctional mitochondria [Federico et al, 2012;Piaceri et al, 2012;Swerdlow, 2012;Chaturvedi and Beal, 2013;Wallace, 2013;Forbes-Hernandez et al, 2014;Nicolson et al, 2014;Pagano et al, 2014;Sodhi et al, 2014;Weisfeld-Adams et al, 2015;Woo et al, 2015]. Mitophagy [Novak, 2012;Ashrafi and Schwarz, 2013;Gomes and Scorrano, 2013;Morris et al, 2014;Pinho et al, 2014;Pinto and Moraes, 2014], a selective subform of autophagy [Choi et al, 2013;Schneider and Cuervo, 2014], is a cellular mechanism for removing dysfunctional mitochondria mediated by PINK1 and PARK2 genes working together Kane and Youle, 2012;Youle and van der Bliek, 2012;Allen et al, 2013;Ashrafi and Schwarz, 2013;Trempe et al, 2013;Redmann et al, 2014;Frake et al, 2015;Pickrell and Youle, 2015].…”

“…An emerging and promising approach to treating these diseases leverages their sensitivity to activation of the master regulator of antioxidant and cytoprotective genes and their products, namely, nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Nrf2/ARE), and mitophagy [Osborne et al, 2014;Pagano et al, 2014;Palikaras and Tavernarakis, 2014;Johnson and Johnson, 2015;Joshi et al, 2015;Matic et al, 2015;Nikoletopoulou et al, 2015;Prasad, 2015;Rai et al, 2015;Denzer et al, 2016;Moos et al, 2016;Suliman and Piantadosi, 2016].…”

Neurodegenerative and Morpho-functional Alterations During Senescence: Positive Modulation by Lipoic Acid and Superoxide Dismutase Ocular Senescence in a Rat Model

“…On the other hand, Down syndrome shows such a complex symptomatology that can be simply ascribed to a redox defect. Also, the mitochondrial-driven pathologies are multi-faceted, therefore linking them to a unique mechanism may become unlikely [27].…”

The relationship among serum levels of manganese superoxide dismutase and mtDNA 8-hydroxy-2'-deoxyguanosine, and dietary antioxidants intake in Type 2 Diabetes

“…It is clear that 8OHdG is an oxidative stress biomarker found to be elevated in patients with diabetes and may contribute to diabetes complications (Pan et al, 2008;Al-Aubaidy et al, 2011). Clinical studies show that serum 8OHdG is measurable by ELISA method and proven to be a reliable biomarker for oxidative DNA damage (Basavarai, et al, 2013;Pagano, et al, 2014).…”