Myocardial Adaptation in Pseudohypoxia: Signaling and Regulation of mPTP via Mitochondrial Connexin 43 and Cardiolipin

Abstract

Therapies intended to mitigate cardiovascular complications cannot be applied in practice without detailed knowledge of molecular mechanisms. Mitochondria, as the end-effector of cardioprotection, represent one of the possible therapeutic approaches. The present review provides an overview of factors affecting the regulation processes of mitochondria at the level of mitochondrial permeability transition pores (mPTP) resulting in comprehensive myocardial protection. The regulation of mPTP seems to be an important part of the mechanisms for maintaining the energy equilibrium of the heart under pathological conditions. Mitochondrial connexin 43 is involved in the regulation process by inhibition of mPTP opening. These individual cardioprotective mechanisms can be interconnected in the process of mitochondrial oxidative phosphorylation resulting in the maintenance of adenosine triphosphate (ATP) production. In this context, the degree of mitochondrial membrane fluidity appears to be a key factor in the preservation of ATP synthase rotation required for ATP formation. Moreover, changes in the composition of the cardiolipin’s structure in the mitochondrial membrane can significantly affect the energy system under unfavorable conditions. This review aims to elucidate functional and structural changes of cardiac mitochondria subjected to preconditioning, with an emphasis on signaling pathways leading to mitochondrial energy maintenance during partial oxygen deprivation.

mPTP Proteins Regulated by Streptozotocin-Induced Diabetes Mellitus Are Effectively Involved in the Processes of Maintaining Myocardial Metabolic Adaptation

“…Other findings suggested that increased membrane fluidity along with stimulation of mitochondrial ATP synthase activity could help to improve myocardial energetics during I/R injury. Due to the lack of energy under hypoxic conditions in the acute phase of the disease, the diabetic myocardium activates endogenous protective mechanisms leading to functional mitochondrial remodeling, which involves changes in the chemical and physical properties of the mitochondrial membrane [28,53]. Several studies demonstrated the positive effect of PC on calcium retention capacity and inhibition of mPTP opening.…”

Homocysteine and Mitochondria in Cardiovascular and Cerebrovascular Systems

“…However, excessive Ca 2+ accumulation by mitochondria stimulates the generation of reactive oxygen species (ROS) and leads to the opening of the mitochondrial permeability transition pore (mPTP), which is closed under physiological conditions. Opening of the mPTP is associated with an abrupt increase in the permeability of the inner membrane, membrane depolarization, inhibition of the ETC and ATP synthesis, matrix swelling, and activation of cell death pathways [ 29 ]. Alterations in the ETC and OXPHOS and related disturbances in Ca 2+ homeostasis and ROS production are closely associated with pathological disorders, such as ischemia–reperfusion injury, myocardial infarction, heart failure [ 30 ] and neurodegenerative diseases, Parkinson’s disease [ 31 ], Alzheimer’s disease [ 32 ], and stroke [ 33 ].…”

Cardiac Connexin-43 Hemichannels and Pannexin1 Channels: Provocative Antiarrhythmic Targets

“…This latter leads to mitochondrial swelling and rupture which then facilitates cardiomyocyte injury and death. The mitochondrial HCs, and perhaps also the Panx1 channels, could regulate pathophysiological processes by inhibiting the mPTP opening [ 202 ].…”