NDUFV2
NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial precursor (EC 7.1.1.2) (NADH-ubiquinone oxidoreductase 24 kDa subunit)
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Mitochondrial reactive oxygen species (ROS) production, specifically at complex I (Cx I), has been widely suggested to be one of the determinants of species longevity. The present study follows a comparative approach to analyse complex I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed using droplet digital PCR (ddPCR) and western blot, respectively. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species.
Keywords
- Complex I
- Droplet digital PCR
- Longevity
- Mammals
- Mitochondria
- NDUFS4 subunit
- NDUFV2 subunit
- VDAC
- Western blot
Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, [[NRXN3]], the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, [[NRXN3]] plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. Our results indicate that the low expression of aging-related [[NRXN3]] may increase AD risk, though the potential mechanism requires further clarification.
MeSH Terms
- Adult
- Aged
- Aging
- Alzheimer Disease
- Down-Regulation
- Gene Expression
- Humans
- Middle Aged
- Nerve Tissue Proteins
- Polymorphism, Single Nucleotide
- Risk Factors
- Young Adult
One of the characteristic features of the aging is dysfunction of mitochondria. Its role in the regulation of metabolism and apoptosis suggests a possible link between these cellular processes. This study investigates the relationship of respiratory complex I with aging-related oxidative stress in the cerebral mitochondria. Deterioration of complex I seen in senescent (26-months old) mitochondria was accompanied by decline in total thiol group content, increase of HNE and HNE-protein adducts as well as decreased content of complex I subunits, GRIM-19 and NDUFV2. On the other hand, decline of complex I might be related with the mitochondrial apoptosis through increased Bax/Bcl-2 cascade in 15-month old animal brains. Higher amount of Bcl-2, Bcl-xL with the lower content of GRIM-19 could maintain to some extent elevated oxidative stress in mitochondria as seen in the senescent group. In the cortical M1 region increased presence of TUNEL cells and more than 20-times higher density of Fluoro-Jade C cells in 26-months old was observed, suggesting significant neurodegenerative effect of aging in the neuronal cells. Our study supports a scenario in which the age-related decline of complex I might sensitize neurons to the action of death agonists, such as Bax through lipid and protein oxidative stimuli in mitochondria. Although aging is associated with oxidative stress, these changes did not increase progressively with age, as similar extent of lesions was observed in oxidative stress markers of the both aged groups.
MeSH Terms
- Aging
- Animals
- Cerebral Cortex
- Electron Transport Complex I
- Lipid Peroxidation
- Male
- Mitochondria
- Oxidative Stress
- Rats
- Rats, Wistar
Keywords
- Aging cortex
- Apoptosis
- Complex I
- Mitochondria
- Oxidative stress