Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Abstract

Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Metabolic network failures in Alzheimer's disease: A biochemical road map

“…We hypothesize that the lipid changes measured in this study reflect alterations in membrane structure and function early in the disease process and suggest a change in lipid rafts, which in turn, cause alterations in Aβ processing [66]. We hypothesize that over time, the changes in lipid membranes, particularly mitochondrial membranes, results in increased lipid oxidation, loss of membrane potential, and changes in membrane transport [79,80]. All of these lipid membrane changes might be reflected as disruption in BCAA as an energy source, production of acylcarnitines, and altered energy substrate utilization.…”

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…NAFLD KEGG pathways were enriched in deiminated proteins in pre-motor PD model plasma-EVs. Interestingly, a link via mitochondrial dysfunction has been made between metabolic syndrome, diabetes, obesity, and non-alcoholic fatty liver disease in the progression of AD, PD, and other neurodegenerative diseases [108]. Furthermore, lipid metabolism (in particular non-alcoholic fatty liver disease pathway) and mitochondrial dysregulation have been identified as molecular pathways and putative biomarkers linked to PD [109].…”

The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction

“…Major preconditioning risk factors such as cardiovascular dysfunction, diabetes, metabolic syndrome, traumatic brain injury, and stroke are shared by the sporadic AD (Biessels and Reagan, 2015;Chakrabarti et al, 2015;de la Torre, 2012;Patterson et al, 2007) and PD (Athauda and Foltynie 2016;Daneshvar et al, 2015;Jabir et al, 2015;Jha et al, 2016;Santiago and Potashkin, 2013;Santiago and Potashkin, 2014), in addition to being associated with AE (Chou et al, 2016;Kalra et al, 2016;Ono and Galanopoulou, 2012;Pitkanen et al, 2015;Verrotti et al, 2012;Waldbaum and Patel, 2010b). These factors are characterized by common brain pathologies such as chronic hypoperfusion (Scholz and Hanefeld, 2016;Zlokovic, 2011), neuro-inflammation, and insulin resistance (Rosales-Corral et al, 2015;Straub 2014;Yamagata et al, 2017), all leading to energy deficiency and oxidative stress.…”