Regulatory Mechanisms of Mitochondrial Volume in the Heart in Response to Physiological and Pathological Stimuli

Abstract

In addition to the critical role in energy metabolism, mitochondria participate in regulating ion homeostasis, redox state, cell proliferation, differentiation, and lipid synthesis. Central to these functions is the inner mitochondrial membrane (IMM), which is crucial for mitochondrial metabolism and overall function. The IMM is densely packed with proteins, comprising over 70% of its mass, that are essential for the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport. The volume of the mitochondrial matrix is a pivotal factor in the structural and functional adaptation of the IMM, both under normal conditions and in response to pathological stress. Various ion transport mechanisms, particularly those involving potassium (K⁺) and calcium (Ca²⁺), regulate the osmotic pressure and volume of the matrix. Minor fluctuations in matrix volume can significantly impact the IMM’s plasticity and stimulate mitochondrial bioenergetics through multiple pathways. However, excessive matrix swelling can disrupt the structural integrity of the IMM by deforming the cristae, potentially leading to cell death mediated by mitochondria. This process is often linked to the opening of mitochondrial permeability transition pores, a phenomenon triggered by elevated matrix Ca²⁺ levels. Despite extensive research, the exact molecular identity of these pores remains unknown. In contrast to Ca²⁺, increased matrix K⁺ levels do not induce pore opening in the absence of elevated Ca²⁺ and may even provide protective effects. Despite significant research efforts, the detailed molecular mechanisms that govern matrix volume changes and IMM structural remodeling in response to energy demands and oxidative stress remain elusive. This review aims to synthesize and discuss existing studies that elucidate the regulatory mechanisms of mitochondrial matrix volume, the remodeling of the IMM, and the interplay between these processes.