From mitochondrial zonation to immune dysregulation: a mechanistic axis in diabetic cardiomyopathy

Figures

• 

  Figure 1. SSM near the cell membrane drive ion transport and contraction; PNM surround the nucleus, linking energy production to nuclear signaling; IFM between myofibers power contraction. SSM fail early in type 2 DbCM, PNM injury patterns remain unclear, and IFM show protein deficits in type 1 DbCM.

• 

  Figure 2. This schematic depicts the spatial distribution of SSM, IFM, and PNM mitochondria in cardiomyocytes, underscoring their distinct roles in ROS generation and functional impairments. Metabolic remodeling characterized by enhanced fatty acid oxidation and reduced glucose utilization elevates the NADH/FADH2 ratio, promoting ETC dysfunction at complexes I/III and RET via a hyperpolarized mitochondrial membrane. This process, amplified by increased ROS production from enzymes such as MAO-A and p66Shc, induces oxidative damage including DNA lesions, Ca2+ overload, and ATP depletion. SSM, IFM, and PNM exhibit differential susceptibilities to Ca2+ overload and mPTP opening, with PNM uniquely regulating nuclear redox signaling. Collectively, these abnormalities disrupt cardiac homeostasis through a feed-forward cycle of mitochondrial dysfunction and oxidative stress, highlighting the convergence of metabolic and redox perturbations in diabetic cardiomyopathy pathogenesis.

• 

  Figure 3. Mitochondrial oxidative stress and dysfunction trigger multi-route release of mtDNA. Released mtDNA acts as a DAMP, activating cGAS-STING and NLRP3 inflammasome pathways, ultimately driving cardiomyocyte fibrosis and maladaptive cardiac remodeling in DbCM.