Mitochondrial Homeostasis in Diabetic Cardiomyopathy: From Dysfunction to Therapeutic Strategies

Figures

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  Figure 1. Schematic of molecular regulatory mechanisms for mitochondrial oxidative metabolism. This diagram shows key mitochondrial oxidative metabolic processes: the TCA cycle, ETC, and oxidative phosphorylation. Acetyl-CoA is oxidized in the TCA cycle to generate NADH and FADH2, which donate electrons to ETC complexes I–IV, pumping protons to form a gradient. Proton re-entry through ATP synthase drives ATP production, converting nutrient energy into usable cellular energy. ETC, electron transport chain; DAG, diacylglycerol; FA-CoA, fatty acyl-coenzyme A; CPT-1, carnitine palmitoyltransferase-1; CPT-2, carnitine palmitoyltransferase-2; NADH, nicotinamide adenine dinucleotide; FAD, flavine adenine dinucleotide, reduced; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Cyt c, cytochrome c; PHD, prolyl hydroxylase. Created in BioRender. Zou, W. (2026) https://BioRender.com/8ywx0u1, accessed on 3 March 2026.

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  Figure 2. Schematic of molecular regulatory mechanisms for mitochondrial fusion and fission. Mitochondrial fusion is mediated by MFN1/2 and OPA1 and negatively regulated by PINK1/Parkin; fission is driven by DRP1 and its receptors FIS1, MFF, and others. The dynamic equilibrium between fusion and fission maintains mitochondrial function and cellular homeostasis. DRP1, dynamin-related protein 1; MFF, mitochondrial fission factor; FIS1, fission1; MID49, mitochondrial dynamics proteins of 49 kDa; MID51, mitochondrial dynamics proteins of 51 kDa; PINK1, PTEN-induced kinase 1; Parkin, E3 ubiquitin–protein ligase parkin; PPA2, phosphatase 2A; MTFP1, mitochondrial fission process 1; OMA1, overlapping with the M-AAA protease 1 homolog; OPA1, optic atrophy 1; MFN1, mitofusin 1; MFN2, mitofusin 2. Created in BioRender. Zou, W. (2026) https://BioRender.com/9ojsyrq, accessed on 3 March 2026.

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  Figure 3. Schematic of molecular regulatory mechanisms for mitophagy. The three primary pathways of mitochondrial autophagy: On the left is the PINK1/Parkin-dependent pathway, where PINK1 recruits Parkin to ubiquitinate outer-mitochondrial-membrane proteins, subsequently recruiting autophagy receptors that bind LC3. On the right is the receptor-mediated pathway, where receptors such as Nix, BNIP3, and FUNDC1 directly bind to LC3/GABARAP. Below is the mitochondrial-derived vesicle (MDV) pathway. Together, these three pathways mediate the selective autophagic degradation of mitochondria. LC3, microtubule-associated protein 1 light chain 3; PINK1, PTEN-induced kinase 1; Parkin, E3 ubiquitin–protein ligase parkin; OMM, outer mitochondrial membrane; MDV, mitochondrial-derived vesicle; BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; NIX, NIP3-like protein X; FUNDC1, FUN14 domain containing 1; GABARAP, gamma–aminobutyric acid receptor-associated protein. Created in BioRender. Zou, W. (2026) https://BioRender.com/epmyj4i, accessed on 3 March 2026.

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  Figure 4. Mechanisms of diabetic cardiomyopathy. Hyperglycemia triggers cardiac metabolic disorders through hyperinsulinemia and insulin resistance, leading to mitochondrial dysfunction and oxidative stress. This subsequently induces inflammation, endoplasmic reticulum stress, and impaired calcium handling, ultimately promoting the development of DCM. RAAS, renin–angiotensin–aldosterone system; ER, endoplasmic reticulum; ROS, reactive oxygen species. Created in BioRender. Zou, W. (2026) https://BioRender.com/cmufxug, accessed on 3 March 2026.

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  Figure 5. Drugs target mitochondrial homeostasis for diabetic cardiomyopathy. SGLT2i, GLP-1RA, and MRA improve DCM by multidimensionally regulating mitochondrial function. At the oxidative metabolism level, SGLT2i and GLP-1RA stabilize mitochondrial Ca2+ homeostasis, reduce oxidative stress, and promote ATP production. In mitochondrial dynamics, all three classes synergistically promote mitochondrial fusion and inhibit excessive fission. Regarding mitochondrial autophagy, they accelerate the clearance of damaged mitochondria by activating both PINK1/Parkin-dependent and FUNDC1-mediated independent pathways, thereby exerting comprehensive cardioprotective effects. DCM, diabetic cardiomyopathy; SGLT2i, sodium–glucose cotransporter 2 inhibitors; GLP-1RA, glucagon-like peptide-1 receptor agonist; MRA, mineralocorticoid receptor antagonists; NHE-1, sodium/hydrogen exchanger; MICU1, mitochondrial calcium uptake 1; MICU2, mitochondrial calcium uptake 2; MCU, mitochondrial calcium uniporter; p53, tumor protein p53; SCO2, synthesis of cytochrome C oxidase 2; MPT pore, mitochondrial permeability transition pore; GSH, glutathione; SOD, superoxide dismutase; NADPH, nicotinamide adenine dinucleotide…