Mitochondrial BMI1 maintains bioenergetic homeostasis in cells.
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.
Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.
Soumyajit
S
Banerjee Mustafi
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Nicolas
N
Aznar
Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.
Shailendra Kumar Dhar
SK
Dwivedi
Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; and.
Prabir Kumar
PK
Chakraborty
Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.
Rumki
R
Basak
Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; and.
Priyabrata
P
Mukherjee
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Pradipta
P
Ghosh
Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; resham-bhattacharya@ouhsc.edu.|Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA.
Resham
R
Bhattacharya
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*
C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1
PNPase; electron transport chain; mitochondrial mRNA