Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

Abstract

Mitochondrial fission is a crucial process in maintaining metabolic homeostasis in normal physiology and under conditions of stress. Its dysregulation has been associated with several metabolic diseases, including, but not limited to, obesity, type 2 diabetes (T2DM), and cardiovascular diseases. Reactive oxygen species (ROS) serve a vital role in the genesis of these conditions, and mitochondria are both the main sites of ROS production and the primary targets of ROS. In this review, we explore the physiological and pathological roles of mitochondrial fission, its regulation by dynamin-related protein 1 (Drp1), and the interplay between ROS and mitochondria in health and metabolic diseases. We also discuss the potential therapeutic strategies of targeting mitochondrial fission through antioxidant treatments for ROS-induced conditions, including the effects of lifestyle interventions, dietary supplements, and chemicals, such as mitochondrial division inhibitor-1 (Mdivi-1) and other mitochondrial fission inhibitors, as well as certain commonly used drugs for metabolic diseases. This review highlights the importance of understanding the role of mitochondrial fission in health and metabolic diseases, and the potential of targeting mitochondrial fission as a therapeutic approach to protecting against these conditions.

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“…Additionally, dynamic balance between fission and fusion are crucial to maintain function and structure of mitochondria. Previous studies have identified that DRP1 is the mitochondrial fission core component, which is gathered into circular structure to mediate mitochondrial fission by mitochondrial cleavage alongside mitochondrial tubules [ 36 ]. OPA1 maintains fused mitochondrial network, and drives inner membrane fusion at the mitochondrial inner membrane [ 37 ].…”

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“…These processes maintain metabolic homeostasis in normal physiology and during cellular stress. Under physiological conditions, mitochondria undergo consistent fission and fusion to ensure homeostasis and energy adaptation but these are disrupted during pathological conditions [ 7 ].…”

“…The accumulation of dysfunctional mitochondria is associated with the overproduction of mROS, mitochondria-controlled apoptosis, and chronic innate immune activation involved in age related diseases [ 6 ]. Mitophagy, which is the process of removing damaged mitochondria is impaired during pathological conditions [ 7 ]. Deregulation of MQC processes and ultimately mitochondrial dysfunction has been implicated in sarcopenia [ 16 ], glaucoma [ 17 ], lung disease [ 18 ], infection, obesity, type 2 diabetes/diabetes kidney disease [ 19 ], hepatic ischemia-reperfusion injury [ 20 ], cardiovascular disease [ 21 ], neurological diseases [ 22 ] and age-related diseases [ 9 , 23 ].…”

“…As ROS have been implicated in pathological conditions, strategies targeting ROS such as lifestyle interventions and dietary supplements are a potential therapeutic focus [ 7 , 9 ]. Healthy lifestyle choices including exercise, diet (eating a diet rich in fibre, fruits and vegetables, unprocessed foods, avoiding too much meat and fat) and dietary supplements have been reported to play a role in MQC, ameliorating mitochondrial dysfunction [ 24 ].…”

“…There are four stages in a mitochondrion's life cycle including: biogenesis (co-ordinated expression of mitochondria and nuclear genes by transcription and translation, import of the products and turnover); fusion/fission (critical processes that regulate the size, number, and function of mitochondria due to energy demand) and degradation (removal of dysfunctional mitochondria through the autophagic process, known as ‘mitophagy’). Mitochondrial-targeted antioxidants may promote mitochondrial fusion, decreasing the expression of fission proteins Drp1 and Fis1, thereby decreasing mitochondrial fission [ 7 ]. Enhancing antioxidant capacity improves mitochondrial function by ameliorating oxidative stress, inhibiting mitochondrial fission, increasing ATP production, and improving insulin sensitivity.…”