Lipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and muscle insulin resistance. Interestingly, mitophagy genes, such as BNIP3L/Nix, has also been linked to lipid metabolism. BNIP3L is an outer mitochondrial pro-apoptotic protein that plays an important role in serving as a mitochondrial autophagy receptor and an indispensable regulator of erythropoiesis. Recent studies from our group demonstrated that BNIP3L is elevated in response to lipid-induced stress leading to mitochondrial dysfunction and impaired insulin signalling. However, the precise mechanisms of BNIP3L activation of such responses are not entirely known.

Given BNIP3L’s role in mitochondrial autophagy, also known as mitophagy, in my thesis, I investigate aberrant mitochondrial turnover as a mechanism leading to impaired myocyte insulin signalling. In a series of gain-of-function and loss-of-function experiments in rodent and human myotubes, I demonstrate that BNIP3L accumulation triggers a series of cellular events, ultimately resulting in dysfunctional mitochondria. I also demonstrate mechanistically how BNIP3L can inhibit insulin signalling via mTOR activation. Finally, I provide evidence that BNIP3L-induced mitophagy and impaired glucose uptake can be reversed by pharmacologically targeting BNIP3L with PRKA activating agents, leading to BNIP3L’s translocation from the mitochondria and sarcoplasmic reticulum to the cytosol, therefore blunting BNIP3L function.

Collectively, the data presented here emphasize the crucial role of proper mitochondrial quality control in maintaining myocyte glucose homeostasis. Furthermore, disruption of mitochondrial quality control pathways, such as under lipotoxicity stress, may lead to pathological conditions, whereby mitophagy becomes a maladaptive response to nutrient storage stress. Therefore, understanding BNIP3L’s role in mitophagy and how it impairs muscle insulin signalling in vitro is essential to further investigate and delineate its importance in both in vivo and human studies, with the ultimate goal being to avert early-onset insulin resistance.