Connexin 43 Role in Mitochondrial Transfer and Homeostasis in the Central Nervous System

ABSTRACT Connexin 43 (Cx43) is a transmembrane protein involved in the assembly of gap junctions (GJs) and hemichannels (HCs), organized structures that allow the transferring of ions and small signaling molecules between cells and/or extracellular environment, thereby contributing to tissue homeostasis intercellular communication. Cx43 has recently been identified within the mitochondria of cells, suggesting that it may have additional functions beyond its canonical role. Most studies of mitochondrial Cx43 (mt‐Cx43) have been limited to cells of the cardiovascular system, where it appears to play a role in ATP production, calcium homeostasis, and the response to oxidative stress. However, its functions within the central nervous system (CNS) are not fully understood. Recently, it has been observed that Cx43‐forming GJs is one of the key mechanisms that cells use for the transfer of organelles, including mitochondria. Cx43‐mediated mitochondrial transfer is crucial in the CNS, supporting cellular homeostasis and neuroprotection under both physiological and pathological conditions. The dual roles of Cx43 in regulating mitochondrial function and in mediating mitochondrial transfer, raise important questions about how it coordinates these mechanisms. Herein, we reviewed recent findings on the importance of Cx43 and mt‐Cx43 in the healthy and altered CNS environment, with the aim of shedding light on its potential role in CNS homeostasis and as a therapeutic target in neurological disorder in which Cx43 plays a predominant function.