Drp1 modulates mitochondrial stress responses to mitotic arrest

Abstract

Antimitotic drugs are extensively used in the clinics to treat different types of cancer. They can retain cells in a prolonged mitotic arrest imposing two major fates, mitotic slippage, or mitotic cell death. While the former is molecularly well characterized, the mechanisms that control mitotic cell death remain poorly understood. Here, we performed quantitative proteomics of HeLa cells under mitotic arrest induced with paclitaxel, a microtubule-stabilizer drug, to identify regulators of such cell fate decision. We identified alterations in several apoptosis-related proteins, among which the mitochondrial fission protein Drp1 presented increased levels. We found that Drp1 depletion during prolonged mitotic arrest led to strong mitochondrial depolarization and faster mitotic cell death as well as enhanced mitophagy, a mechanism to remove damaged mitochondria. Our findings support a new role of Drp1 in orchestrating the cellular stress responses during mitosis, where mitochondrial function and distribution into the daughter cells need to be coordinated with cell fate. This novel function of Drp1 in the cell cycle becomes best visible under conditions of prolonged mitotic arrest.

Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

“…Indeed, enhanced mitochondrial fission is well documented in AD patients and model organisms with a bias toward increased mitochondrial fragmentation ( Calkins et al, 2011 ; Manczak et al, 2011 ; Kandimalla et al, 2016 ; Manczak et al, 2016 ). Similarly, increased mitochondrial ROS production, compromised mitochondrial function, and apoptosis has been associated with excessive mitochondrial fission and mitochondrial structural abnormalities ( Pena-Blanco et al, 2020 ). Given the critical role of mitochondrial dynamics, any defects in the fidelity of the fission machinery may have a devastating impact on redox homeostasis, energy generation, and mitochondrial function.…”

A PKD-MFF signaling axis couples mitochondrial fission to mitotic progression

“…To address the requirement of MFF in mitosis, we first downregulated MFF, the mitochondrial fusion factor OPA1 as a negative control (Cipolat et al, 2004;Park and Cho, 2012), and DRP1 as a positive control (Díaz-Martínez et al, 2014;Peñ a-Blanco et al, 2020) by using specific small interfering RNAs (siRNAs) in HeLa cells (Figures S1A and S1B). As expected DRP1-and MFFdepleted cells displayed fused and elongated mitochondria relative to cells treated with control siRNA where mitochondria were tubular, whereas OPA1 depletion led to a more fragmented mitochondrial phenotype (Figure S1C).…”

The multifaceted role of cell cycle regulators in the coordination of growth and metabolism

“…Multiple lines of evidence have led to the consensus that DRP1‐mediated mitochondrial fission before mitosis is an essential phenomenon. Indeed, extended tubular structures cause defects at the G2‐to‐M transition and can even trigger senescence or apoptotic cell death [ 134 , 155 , 156 ]. Despite the fact that it is true that cells lacking DRP1 are capable of completing cell division, filamentous organelles disturb their equal partition to daughter cells as seen in different cell lines [ 155 , 156 ].…”

“…Indeed, extended tubular structures cause defects at the G2‐to‐M transition and can even trigger senescence or apoptotic cell death [ 134 , 155 , 156 ]. Despite the fact that it is true that cells lacking DRP1 are capable of completing cell division, filamentous organelles disturb their equal partition to daughter cells as seen in different cell lines [ 155 , 156 ]. After the mitotic cycle is achieved, daughter cells rebuild a partially intertwined and fused mitochondrial network caused, in part, by the reactivation of APC/C‐Cdh1 complexes.…”