Cyclin D1 Inhibits Mitochondrial Activity in B Cells

Abstract

Cyclin D1 is a cell cycle regulatory protein that acts at the G1-S transition, following its binding to and activation by the cyclin-dependent kinases 4 or 6. Cyclin D1 is absent from the entire B-cell lineage but is present in a large percentage of 2 types of malignant B-cell hemopathy-mantle cell lymphoma and multiple myelomasuggesting a major role of this protein in the malignancy process. We show here, in an experimental model of cyclin D1 fusion protein transduction in mature B cells, that, cyclin D1 inhibits total mitochondrial activity. Cyclin D1 is localized at the outer mitochondrial membrane, bound to a voltage-dependent anion channel through its central domain, and it competes with hexokinase 2 for binding to this channel. The bound cyclin D1 decreases the supply of ADP, ATP, and metabolites, thereby reducing energy production. This function of cyclin D1 was also reported by others in normal and transformed mammary epithelial cells, suggesting that it may be ubiquitous. Cancer Res; 71(5);

Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells

“…ROS are mainly produced by mitochondria and a family of NADPH oxidases or NOX [24]. We and others have shown that cyclin D1 can negatively regulate mitochondrial respiration [25, 26]. We further analyzed the metabolic profiles of GFP- and D1-GFP-expressing cells using the Seahorse XF96 analyzer which simultaneously records mitochondrial respiration and glycolysis.…”

Metabolic control of the cell cycle

“…On the other hand, in malignant tumors, HKII binds to the voltage-dependent anion channel (VDAC), the most abundant outer mitochondrial membrane (OMM) protein, which mediates the trafficking of metabolites across the OMM. [30][31][32] This interaction allows direct access by HKII to ATP generated by mitochondrial ATP synthase, thereby accelerating phosphorylation of glucose and subsequent funneling of glucose-6-phosphate along the glycolytic pathway; in agreement, pharmacological disruption of the HKII-VDAC interaction inhibits glycolysis. [30][31][32][33] Of note, cyclin D1 was reported to compete with HKII for binding to VDAC, 30 which could negatively affect glycolysis.…”

“…Also, the HKII interaction with VDAC has only been documented in cancer cells to date. 30,33 Whether and how cyclin D1 regulates glycolysis in non-malignant cells and has similar context-dependent effects remains unresolved to date.…”

Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases

“…Cyclin D1 can also exert its effect on mitochondria independently of CDK4 by binding to the voltage-dependent anion channel protein (VDAC) in the outer mitochondrial membrane, thereby preventing VDAC from binding to hexokinase 2 and impairing the access of ADP to the inner mitochondrial membrane 142 . Further observations that cyclin D1 can directly bind additional lipogenic enzymes and mitochondrial proteins 48 point to cyclin D1 as an important regulator of metabolic activities through different pathways 143 .…”