Mitochondrial nanotunnels in cardiac disorders

Mitochondria are essential double-membraned organelles that provide most of the adenosine triphosphate (ATP) required for cardiac contraction and ion homeostasis. Beyond energy production, they regulate Ca²⁺ handling, reactive oxygen species (ROS) signaling, redox balance, and cell survival. Consequently, mitochondrial dysfunction is widely recognized as a central mechanism underlying cardiac disorders, while altered mitochondrial dynamics-the ability of mitochondria to change shape and connectivity-has been associated with diverse myocardial diseases. Yet, the conventional fusion-fission paradigm does not adequately explain how mitochondria, constrained within the rigid sarcomeric lattice of cardiomyocytes, maintain function and quality control. In this highly ordered environment, mitochondrial subpopulations are densely packed and largely immobilized, limiting long-range organelle transport. Recent ultrastructural studies have identified thin double-membrane nanotunnels as potential conduits for communication between distant mitochondria. Experimental studies have identified mitochondrial nanotunnels (MNTs) in cardiomyocytes and reported changes in their abundance or associated communication in selected cardiac models. However, their contribution to metabolic and stress signaling remains incompletely defined. Despite these intriguing observations, the precise role of nanotunnels across cardiac disorders remains uncertain. Key questions include whether their activity is protective or detrimental, how they behave across distinct mitochondrial subpopulations, and whether they contribute to adaptive or maladaptive remodeling under stress. Addressing these gaps is critical for understanding how mitochondrial networks respond to injury. This review brings together current knowledge on cardiac mitochondrial architecture, fusion-fission dynamics, nanotunnel structure and biogenesis, and their potential involvement in cardiac disorders, while highlighting current methodological limitations. Recent studies suggest that nanotunnels are more than passive structural features; they may represent functional pathways for metabolic and signaling integration within the constrained cardiac environment. Mitochondrial nanotunnels may represent potential therapeutic targets once their causal and context-dependent roles in cardiac disorders have been established.