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Review
. 2022 Aug 23:13:957968.
doi: 10.3389/fphys.2022.957968. eCollection 2022.

Mitophagy: A potential therapeutic target for insulin resistance

Peng Ning  1 , Xiaobo Jiang  2 , Jing Yang  1 , Jiaxing Zhang  1 , Fan Yang  1 , Hongyi Cao  1
Affiliations
Review

Mitophagy: A potential therapeutic target for insulin resistance

Peng Ning et al. Front Physiol. .

Abstract

Glucose and lipid metabolism disorders caused by insulin resistance (IR) can lead to metabolic disorders such as diabetes, obesity, and the metabolic syndrome. Early and targeted intervention of IR is beneficial for the treatment of various metabolic disorders. Although significant progress has been made in the development of IR drug therapies, the state of the condition has not improved significantly. There is a critical need to identify novel therapeutic targets. Mitophagy is a type of selective autophagy quality control system that is activated to clear damaged and dysfunctional mitochondria. Mitophagy is highly regulated by various signaling pathways, such as the AMPK/mTOR pathway which is involved in the initiation of mitophagy, and the PINK1/Parkin, BNIP3/Nix, and FUNDC1 pathways, which are involved in mitophagosome formation. Mitophagy is involved in numerous human diseases such as neurological disorders, cardiovascular diseases, cancer, and aging. However, recently, there has been an increasing interest in the role of mitophagy in metabolic disorders. There is emerging evidence that normal mitophagy can improve IR. Unfortunately, few studies have investigated the relationship between mitophagy and IR. Therefore, we set out to review the role of mitophagy in IR and explore whether mitophagy may be a potential new target for IR therapy. We hope that this effort serves to stimulate further research in this area.

Keywords: autophagy; insulin resistance; mitochondrial dysfunction; mitophagy; therapeutic target.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Mitochondrial fission. The protein that regulates mitochondrial fission is mainly Drp1, which is generally localized in the cytoplasm under physiological conditions. Various stimulators result in recruitment and oligomerization of Drp1 to mitochondria by binding its receptors Mff, Fis1, MiD49 and MiD51, and then induce mitochondrial fission.(B) Mitochondrial fusion. Mitochondrial fusion proteins include mainly mitochondrial fusion protein 1 (Mitofusin1, Mfn1), mitochondrial fusion protein 2 (Mitofusin 2, Mfn2) and optic atrophy one protein (OPA1). Mfn1 and Mfn2 are widely expressed in the mitochondrial outer membrane and mediate the fusion of outer membrane of mitochondria. OPA1 is mainly involved in the mitochondrial inner membrane fusion process.
FIGURE 2
FIGURE 2
(A) Mitochondria depolarize and damage themselves in response to various stimuli such as reactive oxygen species (ROS), nutrient deficiency, chemical stimulation, and mtDNA mutation.(B) Mitochondria membrane structure extends.(C) Envelops and seals up the mitochondria to be removed.(D) Forming autophagosomes.(E) The autophagosomes fuse with lysosomes to form autolysosomes. (F) The autolysosomes degrade the mitochondria.
FIGURE 3
FIGURE 3
(A) AMPK/mTOR is a crucial regulatory pathway of autophagy and often acts as the initiation pathway of mitophagy. Under nutrient-rich conditions, mTORC1 strongly inhibits autophagy through direct ULK1 phosphorylation. When the cell is starved or depleted of energy, mTORC1 dissociates from the complex and ULK1 autophosphorylation increases; AMPK promotes autophagy not only by directly activating ULK1 but also by negatively regulating mTORC1 and blocking its inhibition of ULK1.(B) PINK1/Parkin-mediated mitophagy depends on the activity of voltage-dependent anion channels (VDAC1) and P62/SQSTM1, which interact directly with light chain 3 (LC3) to recruit autophagosomes. Damaged mitochondria are enclosed in the autophagosomes and transported to lysosomes for degradation.(C) BNIP3/Nix promote mitophagy through interaction with processed LC3-related molecules at nascent phagophores.(D) Under hypoxia and other conditions, the activity of protein kinase Src, which inhibits the activity of FUNDC1, will also decrease, so as to enhance the activity of FUNDC1 and promote the interaction with LC3, thus affecting mitophagy.
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