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.

Keywords: gap junction; homeostasis; intercellular communication; metabolism; neurological disorder.

Figure 1

Regulation of Cx43 turnover. (a) After synthesis in the endoplasmic reticulum (ER), Cx43 oligomerizes in the Golgi apparatus and is processed in the trans‐Golgi network, before being transported to the plasma membrane. Misfolded or improperly assembled Cx43 proteins in the ER are targeted for degradation via the proteasome. (b) At the membrane, Cx43 can either form gap junctions (GJs) with hemichannels (HCs) from adjacent cells or functions as free HCs that exchange ions and small metabolites with extracellular environment. (c) GJs cluster into dynamic plaques, which undergo continuous remodeling in response to cellular signals. (d) Aged Cx43 proteins at the plasma membrane are internalized into connexosomes and degraded via lysosomal pathways.

Figure 2

Cx43's non‐canonical roles in regulating neurogenesis, mitochondrial function and extracellular vesicles (EVs) dynamics. (a) Cx43 intracellular carboxy‐tail plays a key role in regulating the proliferation and differentiation of neuronal progenitor cells. By interacting with the with Mitogen‑activated protein kinase (MAPK) cascades and extracellular signal‐regulated kinase 1/2 (ERK) signaling pathway, Cx43 modulates neural stem cells (NSCs) quiescence, thereby fostering neurogenesis. (b) In mitochondria, Cx43 is localized on the inner mitochondrial membrane (IMM), where it governs the flux of ions, including K⁺ and H⁺. Additionally, Cx43 facilitates Ca²⁺ transfer from the mitochondrial‐associated membranes (MAMs) to the mitochondria, enhancing ATP production and supporting mitochondrial function. (c) Cx43 hemichannels (HCs) are also located on EV membrane, where they can be transferred from donor to recipient cells, impacting cellular homeostasis. This process may lead to the formation of gap junctions (GJs) between EVs and recipient cells, or fusion of EVs containing pro‐inflammatory cytokines and Cx43 HCs with recipient cells. This fusion allows recipient cells to incorporate functional Cx43 HCs, enabling further cytokines release, thereby promoting neuroinflammation.

Figure 3

Role of mitochondrial Cx43. (a) Mitochondrial Cx43 (mt‐Cx43) plays a crucial role in mitochondrial function among which the response to oxidative stress; mt‐Cx43 expression increases and modulates mitochondrial dynamics, supporting protective mitochondrial fission. (b) mt‐Cx43 also regulates ATP production by facilitating the exchange of ions such as potassium (K⁺), critical for maintaining mitochondrial membrane potential and energy metabolism. Gap19 inhibition of Cx43 significantly reduced the entrance of K⁺ ions. (c) The import of Cx43 into mitochondria is regulated by TOM complex and HSP90 inhibition with Geldanamycin has been shown to impair this process, leading to a reduction in mt‐Cx43 levels and affecting mitochondrial function. (d) Calcium (Ca²⁺) ions flux is also regulated by mt‐Cx43, which interacts with mitochondrial‐associated membranes (MAMs) to mediate exchange of Ca²⁺ between ER and mitochondria; use of Gap27, a Cx43 hemichannel blocker, has been shown to decrease Ca²⁺ entry into mitochondria, further emphasizing the role of mt‐Cx43 in maintaining Ca²⁺ homeostasis.

Figure 4

Different mechanisms of mitochondrial transfer. (a) Healthy donor cells can transfer their mitochondria through tunneling nanotubes (TNTs) to recipient cells, that possess impaired mitochondria. (b) Donor cells secrete extracellular vesicles (EVs) containing mitochondria that are captured by recipient cells through endocytosis. (c) Donor cells can also release free mitochondria in the extracellular environment, where recipient cells engulf them through a phagocytic mechanism. (d) Mitochondrial transfer can be Connexin 43 (Cx43)‐mediated, with donor cells that move mitochondria towards recipient cells through Cx43‐based GJs. (e) A small Cx43 isoform, GJA1‐20K, is involved in promoting mitochondria transfer between cells via TNTs.