The mitophagy receptor Bcl-2–like protein 13 stimulates adipogenesis by regulating mitochondrial oxidative phosphorylation and apoptosis in mice

Abstract

Edited by Jeffrey E. Pessin Metabolic programming of bone marrow stromal cells (BMSCs) could influence the function of progenitor osteoblasts or adipocytes and hence determine skeletal phenotypes. Adipocytes predominantly utilize oxidative phosphorylation, whereas osteoblasts use glycolysis to meet ATP demand. Here, we compared progenitor differentiation from the marrow of two inbred mouse strains, C3H/HeJ (C3H) and C57BL6J (B6). These strains differ in both skeletal mass and bone marrow adiposity. We hypothesized that genetic regulation of metabolic programs controls skeletal stem cell fate. Our experiments identified Bcl-2-like protein 13 (Bcl2l13), a mitochondrial mitophagy receptor, as being critical for adipogenic differentiation. We also found that Bcl2l13 is differentially expressed in the two mouse strains, with C3H adipocyte progenitor differentiation being accompanied by a >2-fold increase in Bcl2l13 levels relative to B6 marrow adipocytes. Bcl2l13 expression also increased during adipogenic differentiation in mouse ear mesenchymal stem cells (eMSCs) and the murine preadipocyte cell line 3T3-L1. The higher Bcl2l13 expression correlated with increased mitochondrial fusion and biogenesis. Importantly, Bcl2l13 knockdown significantly impaired adipocyte differentiation in both 3T3-L1 cells and eMSCs. Mechanistically, Bcl2l13 knockdown reprogrammed cells to rely more on glycolysis to meet ATP demand in the face of impaired oxidative phosphorylation. Bcl2l13 knockdown in eMSCs increased mitophagy. Moreover, Bcl2l13 prevented apoptosis during adipogenesis. Our findings indicate that the mitochondrial receptor Bcl2l13 promotes adipogenesis by increasing oxidative phosphorylation, suppressing apoptosis, and providing mitochondrial quality control through mitophagy. We conclude that genetic programming of metabolism may be important for lineage determination and cell function within the bone marrow.

Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

“…In contrast to most stem cells, which have immature mitochondria, stem cells undergoing differentiation usually develop mature or specialized mitochondrial networks. MSCs undergoing differentiation display elongated and interconnected mitochondria accompanied by significantly decreased Drp1 and markedly increased OPA1 expression, indicating that mitochondrial fusion is conducive to MSC differentiation into adipocytes and osteocytes (Feng et al, 2019;Fujiwara et al, 2019). Similarly, Forni et al induced osteogenesis and adipogenesis in MSCs and demonstrated enhanced mitochondrial biogenesis and network restructuring via mitochondrial fusion mediated by Mfn1 and Mfn2 during the early stages of induction (Forni et al, 2016).…”

Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary renal cell carcinoma

“…Mitochondrial dynamics and biogenesis, which is also regulated by BCL2L13, could facilitate the browning process of preadipocytes [ 44 ]. Moreover, low expression of BCL2L13, which was related to weakened oxidative phosphorylation and enhanced glycolysis, was often found in cancer cells [ 45 , 46 ]. Thus, the cellular functions of BCL2L13 might have latent impact on the poor prognosis of ccRCC and pRCC.…”

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

“…BCL2L13 is constitutively expressed in the human fetus and promotes embryonic development [ 124 ]. Additionally, it has been shown that BCL2L13 has a role in the regulation of energy metabolism and fat homeostasis [ 125 ].…”