Energetic microdomains and the vascular control of neuronal and muscle excitability: Toward a unified model

Ion channels are often depicted as autonomous membrane switches, yet their function depends on upstream vascular and mitochondrial processes that deliver ATP to maintain the ionic gradients essential for cellular excitability. Here, we propose a unifying framework, in the form of a capillary-mitochondria-ion channel (CMIC) axis, that links microvascular architecture to beat-to-beat performance in the heart and spike-to-spike behaviour in the brain. In this formulation, capillaries define the spatial resolution of oxygen and energy substrate delivery, while mitochondria serve as the critical intermediary that couples vascular supply to ion channel performance. CMIC coupling is critical in both cardiac function, where each cycle initiates with an electrical spike in pacemaking cells, and neural activity, where electrical spikes encode language, memories and other cognitive processes. Both neurons and cardiomyocytes have limited metabolic reserves, making them vulnerable to microvascular changes. Accordingly, these shared energetic demands, the brain and heart, exhibit similar microvascular topologies where capillary density scales with local metabolic demand. The myocardium is far more densely vascularized than the cerebral cortex, consistent with the higher energetic cost of pacemaking and contraction relative to individual neuronal spikes. Within this axis, mitochondria shape ATP waveforms to power rapid ionic gradients and Ca²⁺ cycling. Changes in any CMIC component, such as capillary rarefaction or mitochondrial dysfunction, alter energetics and thus cellular excitability, with effects ranging from adaptive to pathological depending on severity. Recognizing excitability as a product of vascular-initiated processes shifts the therapeutic focus toward preserving microvasculature function, retuning mitochondria-channel coupling and restoring capillary signalling.