Diabetes Metab J.  2024 Jul;48(4):503-517. 10.4093/dmj.2023.0213.

Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases

• Tang S
• Hao D
• Ma W
• Liu L
• Gao J
• Yao P
• Yu H
• Gan L
• Cao Y

• KMID: 2558033
• DOI: http://doi.org/10.4093/dmj.2023.0213

Abstract

Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca²⁺ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

Keyword

Diabetes mellitus; Heart diseases; Mitophagy; Obesity; Parkin protein; PTEN-induced putative kinase

Figure

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  Fig. 1. PTEN-induced putative kinase 1 (PINK1)/Parkin-independent pathway in mitophagy. The diagram shows the classical mitophagy pathway mediated by receptors and adapters. Receptors-mediated mitophagy includes BCL2 interacting protein 3 like (NIX; also named BNIP3L), BCL2 interacting protein 3 (BNIP3), FUN14 domain containing 1 (FUNDC1), autophagy and beclin 1 regulator 1 (AMBRA1), HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1), and prohibitin 2 (PHB2)-mediated mitophagy. These mediators are almost outer mitochondrial membrane (OMM) proteins, with light chain 3 (LC3)-interacting regions (LIRs) responsible for LC3 recognition and mitophagy initiation. Adapters-mediated mitophagy includes NBR1 autophagy cargo receptor (NBR1), optineurin (OPTN), p62, Tax1 binding protein 1 (TAX1BP1), and calcium binding and coiled-coil domain 2 (NDP52)-mediated mitophagy. These adapters are not localized on OMM except PHB2 and are activated by the ubiquitination of OMM proteins. Also, they can recognize LC3 with LIRs, thus initiating mitophagy. Fig. 1 is created with BioRender.com. IMM, inner mitochondrial membrane.

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  Fig. 2. PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway in mitophagy. The diagram shows the classical mitophagy pathway mediated by PINK1 and Parkin. In basal condition, PINK1 anchors on the outer mitochondrial membrane (OMM) and extends to the inner mitochondrial membrane (IMM), where PINK1 is cleaved as the N-terminal–cleaved PINK1 (ΔN-PINK1), the mature form, by presenilin associated, rhomboid-like (PARL) activity on IMM. After mitochondrial damage, PINK1 cleavage is impaired, leading to increased levels of full-length PINK1 (FL-PINK1). FL-PINK1 accumulation on OMM activates phosphokinase activity, recruits Parkin from the cytoplasm to the mitochondrial membrane, and further increases the phosphorylated- Parkin (p-Parkin) level. Consequently, the elevated p-Parkin level will ubiquitinate OMM proteins and further recruit P62 to these dysfunctional mitochondria to initiate mitophagy. Fig. 2 is created with BioRender.com. TOM, translocase of the outer mitochondrial membrane; P, phosphorylation; Ub, ubiquitin; S, substrates\proteins on mitochondria.

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  Fig. 3. Upstream regulation on Parkin and PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy in obesity and type 2 diabetes mellitus. Parkin regulation: The C-type lectin domain family 16 member A (Clec16a)-ring finger protein 41 (Nrdp1)-ubiquitin specific peptidase 8 (Usp8) complex could induce cellular reactive oxygen species (ROS) through increased Clec16a levels due to the proteosomal inhibition of Nrdp1. Excessive ROS and endoplasmic reticulum (ER) stress activate p53 thus inhibiting Parkin phosphorylation (p-Parkin), with a consequent mitophagy suppression. Serine/threonine protein phosphatase 2A (PP2A) inhibition induced by high-fat diet (HFD) will also decrease p-Parkin levels. Mammalian sterile 20-like kinase 1 (Mst1) is a negative regulator of Parkin expression via the AMP-activated protein kinase (AMPK)/p-AMPK pathway, and long non-coding RNA (lncRNA) small nucleolar RNA host gene 17 (SNHG17) is reported to modulate the ubiquitination of Mst1. PINK1 regulation: PINK1 translation is regulated by forkhead box O3a (FOXO3a) acetylation and bromodomain containing 4 (BRD4)-acetylated histone H3 lysine 27 (H3K27ac) binding to the PINK1 promoter, as FOXO3a acetylation and H3K27 acetylation are significantly increased in HFD-fed mice, leading to the decreased PINK1 messenger RNA (mRNA) and protein level. In addition, an elevated level of tumor necrosis factor, alpha-induced protein 8-like 1 (Tipe1) exacerbates proteosomal activity of prohibitin 2 (PHB2), and the consequent lower level of PHB2 will inhibit PINK1 and Parkin expression, thus suppressing PINK1/Parkin-mediated mitophagy. Fig. 3 is created with BioRender.com. TXNIP, thioredoxin-interacting protein; Ac, acetylation; P, phosphorylation.

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  Fig. 4. Upstream regulation on receptors and adapters-mediated mitophagy in obesity and type 2 diabetes mellitus. (1) FUN14 domain containing 1 (FUNDC1) regulation. FUNDC1-mediated mitophagy is suppressed during high-fat diet (HFD) feeding through the long non-coding RNA (lncRNA) maternally expressed 3 (MEG3)-Rac family small GTPase 1 (Rac1) pathway, as decreased lncRNA MEG3 level lessens Rac1 inhibition, thus increasing FUNDC1 dephosphorylation and decreasing FUNDC1 phosphorylation. The F-box domain of F-box and leucine rich repeat protein 2 (FBXL2) combines with FUNDC1 and regulates FUNDC1-related mitophagy. (2) BCL2 interacting protein 3 (BNIP3) regulation. The suppressed brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway inhibits BNIP3-mediated mitophagy and the activated nuclear receptor 4A1 (NR4A1)/DNA-dependent protein kinase, catalytic subunit (DNA-PKcs)/p53 pathway. Decreased serine/threonine kinase 3 (STK3)/STK4 expression is responsible for BNIP3-mediated mitophagy repression, while the BNIP3 reduction could further reduce the STK3/STK4 level. (3) BCL2 interacting protein 3 like (NIX) regulation. Protein kinase (PKA) participants in NIX phosphorylation, as a lower level of PKA, is associated with decreased inhibitory NIX phosphorylation, leading to excessive mitophagy in obesity. (4) FOX regulation. Inhibitory phosphorylation of forkhead box O1 (FoxO1) is increased by Akt kinase 2 (AKT2)/AMP-activated protein kinase (AMPK)-p-FoxO1 signal pathway. And FoxO1 acetylation is elevated due to sirtuin 1 (SIRT1) suppression in type 2 diabetes mellitus. The translocation of FoxO3a from the cytoplasm to mitochondria is repressed by SIRT6 suppression. In addition, FoxO3a reduction is an upstream regulator of NIX-mediated mitophagy through the cyclic adenosine monophosphate (cAMP)/PKA pathway. (5) Optineurin (OPTN) regulation. OPTN-mediated mitophagy is activated in diabetic mice. Fig. 4 is created with BioRender.com. LRR1, leucine-rich repeat protein 1; P, phosphoryl,tion; Ub, ubiquitin; Ac, acetylation; mtROS, mitochondrial reactive oxygen species; MMP, mitochondrial membrane potential; ER, endoplasmic reticulum; MAM, mitochondria-associated endoplasmic reticulum membrane.

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