Favourable metabolic profile sustains mitophagy and prevents metabolic abnormalities in metabolically healthy obese individuals

Abstract

BackgroundObesity-mediated oxidative stress results in mitochondrial dysfunction, which has been implicated in the pathogenesis of metabolic syndrome and T2DM. Recently, mitophagy, a cell-reparative process has emerged as a key facet in maintaining the mitochondrial health, which may contribute to contain the metabolic abnormalities in obese individuals. However, the status of mitophagy in metabolically healthy obese (MHO) and metabolically abnormal diabetic obese (MADO) subjects remains to be elucidated. Hence, the present study aims to unravel the alterations in mitochondrial oxidative stress (MOS) and mitophagy in these subjects.Methods60 subjects including MHNO (metabolically healthy non-obese), MHO and MADO were enrolled as per the Asian criteria for obesity (n = 20 each). Biochemical parameters, MOS indices, transcriptional and translational expression of mitophagy markers (PINK1, PARKIN, MFN2, NIX, LC3-II, and LAMP-2), and transmission electron microscopic (TEM) studies were performed in peripheral blood mononuclear cells.ResultsThe MHO subjects displayed a favorable metabolic profile, despite accompanied by an increased adiposity as compared to the MHNO group; while MADO group exhibited several metabolic abnormalities, inspite of similar body composition as MHO subjects. A progressive rise in the MOS was observed in MHO and MADO subjects as compared to the MHNO group, and it showed a positive and significant correlation with the body composition in these groups. Further, mitophagy remained unaltered in the MHO group, while it was significantly downregulated in the MADO group. In addition, TEM studies revealed a significant increase in the percentage of damaged mitochondria in MADO patients as compared to other groups, while MHO and MHNO groups did not show any significant alterations for the same.ConclusionA favorable metabolic profile and moderate levels of MOS in the MHO group may play a crucial role in the sustenance of mitophagy, which may further limit the aggravation of MOS, inflammation, and emergence of metabolic aberrations in contrast to MADO subjects, who exhibited multiple metabolic abnormalities and attenuated mitophagy. Therefore, these MHO subjects are likely to be at a lower risk of developing metabolic syndrome and T2DM.

Cadmium-induced oxidative stress in Meretrix meretrix gills leads to mitochondria-mediated apoptosis

“…Mitochondria are the key intracellular targets for Cd stress (Bhansali et al, 2017), and Cd exposure can damage the integrity of the mitochondria in aquatic organisms, both structurally and functionally (Adiele et al, 2011) Through the electron transport chain of the mitochondria, O 2 •− generates H 2 O 2 , which is then split by catalase into water and oxygen or is partially reduced to hydroxide radical (•OH) in a Fenton reaction, causing a wider cellular oxidative damage (Feng et al, 2014) Bivalves are widely distributed in the water ecosystem. As these animals are lter feeders with poor locomotion ability, they are rather sensitive to the contamination of the aquatic environment by toxic metals, making them a group of important animals for aquatic toxicology research and for the evaluation of pollution by toxic metals (Chandurvelan et al, 2015;Chen et al, 2020;Ji et al, 2019).…”

Sonodynamic therapy inhibits palmitate-induced beta cell dysfunction via PINK1/Parkin-dependent mitophagy

“…However, defective mitophagy, which might be caused by long-term oxidative stress, is a common feature of several diseases, such as diabetes, atherosclerosis and neurodegenerative disease 46–48 . Defective mitophagy occurs in the beta cells of obese T2DM patients, and PA treatment can lead to the dysfunction of mitophagy in beta cells in vitro 47 . In addition, defective mitophagy contributes to the production of mitochondrial ROS, the activation of NLRP3-dependent proinflammatory responses and the exacerbation of lipotoxicity 49 .…”

“…In this study, we found that PA inhibited the transcription of PINK1, thus blocking the recognition of damaged mitochondria by autophagosomes. The PINK1/Parkin pathway is one of the important signaling pathways initiating the mitophagy of mitochondria with a low Δψm 47 . Full-length PINK1 (60 kDa) can be inserted into mitochondria but with different outcomes.…”

Obesity, metabolic health and omics: Current status and future directions

“…Targeted gene expression analyses of the MHO phenotype have been much more common. In one study, five out of six investigated mitophagy genes showed no significant differences in expression between MHO and metabolically healthy non-obese subjects[ 38 ]. The authors concluded that unaltered mitophagy allowed the control of oxidative stress and inflammation, leading to improved mitochondrial function and preserved insulin sensitivity in MHO subjects.…”