Connexin 43 is required for the maintenance of mitochondrial integrity in brown adipose tissue

Abstract

We investigated the role of connexin 43 (Cx43) in maintaining the integrity of mitochondria in brown adipose tissue (BAT). The functional effects of Cx43 were evaluated using inducible, adipocyte-specific Cx43 knockout in mice (Gja1 adipoqKO) and by overexpression and knockdown of Cx43 in cultured adipocytes. Mitochondrial morphology was evaluated by electron microscopy and mitochondrial function and autophagy were assessed by immunoblotting, immunohistochemistry, and qPCR. The metabolic effects of adipocyte-specific knockout of Cx43 were assessed during cold stress and following high fat diet feeding. Cx43 expression was higher in BAT compared to white adipose tissue. Treatment with the β3-adrenergic receptor agonist CL316,243 increased Cx43 expression and mitochondrial localization. Gja1 adipoqKO mice reduced mitochondrial density and increased the presence of damaged mitochondria in BAT. Moreover, metabolic activation with CL316,243 further reduced mitochondrial integrity and upregulated autophagy in the BAT of Gja1 adipoqKO mice. Inhibition of Cx43 in cultured adipocytes increased the generation of reactive oxygen species and induction of autophagy during β-adrenergic stimulation. Gja1 adipoqKO mice were cold intolerant, expended less energy in response to β3-adrenergic receptor activation, and were more insulin resistant after a high-fat diet challenge. Collectively, our data demonstrate that Cx43 is required for maintaining the mitochondrial integrity and metabolic activity of BAT.

Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury

“…The role of GJA1-20k in cardiac metabolism and muscle protection during stress. It has been reported that siRNA-mediated knockdown of Cx43 mRNA in adipocytes, which knocks down the smaller isoforms as well (34), reduces mitochondrial content while increasing oxidative stress (47). Our results in Figures 4-7 are consistent with this earlier finding and suggest that increased GJA1-20k enhances mitochondrial biogenesis and reduces ROS production, which is important for survival of the stressed myocardium (48).…”

Astrocytes‐derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1‐20 k

“…GJ alpha 1 (GJA1; also known as Connexin 43, Cx43) protein is the most widely expressed and important GJ protein in the mammalian central nervous system. GJA1 is extremely important for maintaining mitochondrial integrity (Kim, Kwon, Im, et al, 2017). In the blockade of GJA1 to mitochondrial membrane transfer, myocardial hypoxia injury induced by cobalt chloride (CoCl 2 ) can be aggravated (Pecoraro, Pinto, & Popolo, 2018), whereas in myocardial cells pretreated with ischemia-reperfusion injury, the expression of mitochondrial GJA1 is significantly increased (Bell, Shakespeare, Smith, et al, 2018).…”

Expressional Patterns of Connexin Isoforms in the Rat Epididymal Fat during Postnatal Development

“…A limited number of researches have demonstrated the presence and possible biological function of Cx isoforms in the epididymal fat ( Zhu et al, 2016 ; Kim et al, 2017 ). Yanagiya et al (2007) have demonstrated that functional inhibition of gap junctional complex by 18)-glycyrrhetinic acid results in expressional reduction of several molecules involving in mitotic clonal expansion during adipogenesis.…”

“…Some Cx isoforms are present in a broad range of tissues and/or cell types, while expression of certain Cx isoforms is restricted into specific cell types ( Pointis et al, 2005 ). Even though it is not largely examined, expression of Cx isoforms and possible role of Cx isoforms in fat tissues have been studied ( Burke et al, 2014 ; Kim et al, 2017 ). Among the male reproductive tract, expression of Cx isoforms in the testis and epididymis has been extensively evaluated by other and our previous researches ( Hejmej et al, 2007 ; Han & Lee, 2013 ).…”