The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

Figures

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  Figure 1. Interconnections between mitophagy, mitochondrial dynamics, and mitochondrial biogenesis in DCM. Damaged and malfunctional mitochondria are isolated via mitochondrial fission, merged with lysosome, and digested through mitophagy. Healthy parts of mitochondria are returned to the mitochondrial network through mitochondrial fusion. Mitochondrial fission is mediated by Drp1 and Fis1, fusion––Mfn1 and 2, OPA1, while conventional mitophagy is guided by Atg7 (Autophagy-Related Protein 7) and LC3 (Autophagy-Related Ubiquitin-Like Modifier LC3 A), and alternative––by Ulk1 (unc51 like kinase 1)- and Rab9 (Ras-related protein Rab-9)-dependent mechanism. The adequate mitochondrial pool is supported via generation of new mitochondria, which is regulated by transcription factors (such as PPARα/γ) and cofactors (such as PGC1α), and sustained the supply of energy to the myocardium. The imbalance between mitochondrial dynamics, mitophagy, and mitochondrial biogenesis leads to metabolic dysregulation and cardiomyocytes’ damage. The effects of the diabetes, high fat (HF), and high glucose (HG) conditions on the key players are depicted with blue, yellow and red arrows, respectively.

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  Figure 2. Influence of diabetes on mitochondrial Ca2+ homeostasis. Diabetes inhibits key players, indicated by red arrows. Mitochondria and ER/SR are linked by several proteins resulting in optimised Ca2+ flows between these two organelles. GRP75 and Mfn2 serve as anchoring proteins, narrowing the MAMs (mitochondrial associated membranes) space between IP3R2/VDAC and RyR2. The mPTP opening can be induced by increased ROS, Ca2+ or decreased ΔΨm, which is resulting in the release of the mitochondrial content including pro-apoptotic proteins. Abnormal expression of proteins of the MCU results in diminished Ca2+ uptake with reduced [Ca2+]m. This [Ca2+]m reduction contributes to the occurrence of mitochondrial dysfunctions, in particular, a decrease in the PDC activity, followed by decreased mitochondrial bioenergetics. Consequently, the insufficient ATP content cannot match the energy demand for the cardiomyocyte contraction required for the normal functioning of the heart.

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  Figure 3. Involvement of mitochondrial dysfunction in diabetic cardiomyopathy. In the diabetic condition, ATP is mostly generated from FAO instead of glucose, which leads to OXPHOS impairment and generates more ROS. Disrupted Ca2+ handling leads to mitochondrial Ca2+ overload and mPTP opening, which causes mitochondrial respiratory dysfunction, increased ROS production and a number of consequential effects (such as increased DNA damage, apoptosis rate, inflammation and others). Mitophagy plays a protective role, removing damaged mitochondria and attenuating mitochondrial dysfunction.