IKKß stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.

AIMS: The mitochondrial dynamics protein Mitofusin 2 (MFN2) coordinates critical cellular processes including mitochondrial bioenergetics, quality control, and cell viability. The NF-κB kinase IKKß suppresses mitochondrial injury in doxorubicin cardiomyopathy, but the underlying mechanism is undefined. METHODS AND RESULTS: Herein, we identify a novel signalling axis that functionally connects IKKß and doxorubicin cardiomyopathy to a mechanism that impinges upon the proteasomal stabilization of MFN2. In contrast to vehicle-treated cells, MFN2 was highly ubiquitinated and rapidly degraded by the proteasomal-regulated pathway in cardiac myocytes treated with doxorubicin. The loss of MFN2 activity resulted in mitochondrial perturbations, including increased reactive oxygen species (ROS) production, impaired respiration, and necrotic cell death. Interestingly, doxorubicin-induced degradation of MFN2 and mitochondrial-regulated cell death were contingent upon IKKß kinase activity. Notably, immunoprecipitation and proximity ligation assays revealed that IKKß interacted with MFN2 suggesting that MFN2 may be a phosphorylation target of IKKß. To explore this possibility, mass spectrometry analysis identified a novel MFN2 phospho-acceptor site at serine 53 that was phosphorylated by wild-type IKKß but not by a kinase-inactive mutant IKKßK-M. Based on these findings, we reasoned that IKKß-mediated phosphorylation of serine 53 may influence MFN2 protein stability. Consistent with this view, an IKKß-phosphomimetic MFN2 (MFN2S53D) was resistant to proteasomal degradation induced by doxorubicin whereas wild-type MFN2 and IKKß-phosphorylation defective MFN2 mutant (MFNS53A) were readily degraded in cardiac myocytes treated with doxorubicin. Concordantly, gain of function of IKKß or MFN2S53D suppressed doxorubicin-induced mitochondrial injury and cell death. CONCLUSIONS: The findings of this study reveal a novel survival pathway for IKKß that is mutually dependent upon and obligatory linked to the phosphorylation and stabilization of the mitochondrial dynamics protein MFN2.

The association between loneliness or social isolation and food and eating behaviours: A scoping review.

Loneliness or social isolation and food/eating behaviours have important health consequences and there are rationales for why they could interact. Loneliness and dietary behaviours are recognised as health determinants and targets for interventions at individual, group and population levels. However, there are currently no research reviews investigating associations between these areas. This scoping review synthesized evidence investigating loneliness or social isolation and food/eating behaviours in people aged over 16 years in high-income countries. A systematic search of five databases from 2000 was conducted using predetermined search terms. Dissertation database and backwards citation searches were also conducted. Full text screening of 254 articles/theses resulted in inclusion of three qualitative and 26 quantitative studies, with eight conducted in COVID-19 lockdowns. Almost all studies reported a relationship between loneliness/social isolation and eating behaviours usually considered harmful such as low fruit and vegetable intake and lower diet quality. Qualitative research also supports the detrimental influence of loneliness or social isolation on eating. Study quality was considered, and interpretation and comparison of results was complicated by use of varying methods. Better awareness and understanding of the relationship between these complex aspects of health is needed to inform the development of interventions and practice of nutrition and mental health practitioners, policymakers, researchers and end-users.