Mitochondrial BMI1 maintains bioenergetic homeostasis in cells

Abstract

The polycomb complex proto-oncogene BMI1 [B lymphoma Mo-MLV insertion region 1 homolog (mouse)] is essential for self-renewal of normal and cancer stem cells. BMI1-null mice show severe defects in growth, development, and survival. Although BMI1 is known to exert its effect in the nucleus via repression of 2 potent cell-cycle regulators that are encoded by the Ink4a/Arf locus, deletion of this locus only partially rescues BMI1-null phenotypes, which is indicative of alternate mechanisms of action of BMI1. Here, we show that an extranuclear pool of BMI1 localizes to inner mitochondrial membrane and directly regulates mitochondrial RNA (mtRNA) homeostasis and bioenergetics. These mitochondrial functions of BMI1 are independent of its previously described nuclear functions because a nuclear localization-defective mutant BMI1 rescued several bioenergetic defects that we observed in BMI1-depleted cells, for example, mitochondrial respiration, cytochrome c oxidase activity, and ATP production. Mechanistically, BMI1 coprecipitated with polynucleotide phosphorylase, a ribonuclease that is responsible for decay of mtRNA transcripts. Loss of BMI1 enhanced ribonuclease activity of polynucleotide phosphorylase and reduced mtRNA stability. These findings not only establish a novel extranuclear role of BMI1 in the regulation of mitochondrial bioenergetics, but also provide new mechanistic insights into the role of this proto-oncogene in stem cell differentiation, neuronal aging, and cancer.-Banerjee Mustafi, S., Aznar, N., Dwivedi, S. K. D., Chakraborty, P. K., Basak, R., Mukherjee, P., Ghosh, P., Bhattacharya, R. Mitochondrial BMI1 maintains bioenergetic homeostasis in cells.

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction

“…Polycomb-related BMI1 protein is necessary for the maintenance of several adult stem cell populations, mainly through its capacity to inhibit senescence-related genes and to regulate mitochondrial function. 48, 49 In-depth analysis of how BMI1 acts has nonetheless allowed description of specific tissue-related functions. In mesenchymal cells, BMI1 inhibits the expression of key chemokines from the senescence-associated secretory phenotype.…”

BMI1 in the heart: Novel functions beyond tumorigenesis

“…It has been illustrated that cells lacking BMI1 exhibit mitochondrial dysfunction, the disturbance of reactive oxygen species (ROS) homeostasis, and the activation of DNA damage response (DDR) pathway; correspondingly, antioxidants or interruption of DDR pathway can rescue the deficiency of BMI1 [35] . BMI1 was also found present in the inner mitochondrial membrane, beyond its previously described nuclear localization, and participated in the direct modulation of mitochondrial bioenergetics; meanwhile, BMI1 deficiency resulted in reduced stability of mitochondrial RNA and increased ribonuclease activity of polynucleotide phosphorylase [36] . With regard to the cardiovascular field, Herrero and colleagues provided evidence on the contribution of BMI1 in the turnover of adult progenitor cells in response to cardiac oxidative stress [37] : in the cardiac steady-state, BMI1 mainly binds to the canonical cell fate-related DNA targets in cardiac progenitors; while in response to an accumulation of ROS triggered by oxidative stress, BMI1 delocalized from DNA canonical targets to the non-canonical ones and regulated the terminal differentiation of cardiac stem cells to CMs, and it has been observed that 25% of the CM-committed cells in adult mice are derived from BMI1 + cardiac cells.…”

Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice

“…Bmi1 is important for the self-renewal of stem cells. Bmi1 modulates mitochondrial function (41), ROS generation, and DNA double-strand break repair (42), and regulates the function and apoptosis of various types of cells, such as stem cells and cancer cells (43,44). Therefore, the present study examined whether Shh pathway activation regulates Bmi1 in diabetic EPCs.…”