Mitochondrial network structure homeostasis and cell death

Abstract

Mitochondria are the major cellular energy‐producing organelles and intracellular source of reactive oxygen species. These organelles are responsible for driving cell life and death through mitochondrial network structure homeostasis, which is determined by a balance of fission and fusion. Recent advances revealed that a number of components of the fission and fusion machinery, including dynamin‐related protein 1 (Drp1), mitofusin1/2 (Mfn1/2) and Optic atrophy 1 (OPA1), that have been implicated in mitochondrial shape changes are indispensible for autophagy, apoptosis and necroptosis. Drp1 is the main regulator of mitochondrial fission and has become a key point of contention. The controversy focuses on whether Drp1 is directly involved in the regulation of cell death and, if involved, whether is it a stimulator or a negative regulator of cell death. Here, we examine the relevance of the homeostasis of the mitochondrial network structure in 3 different types of cell death, including autophagy, apoptosis and necroptosis. Furthermore, a variety of cancers often exhibit a fragmented mitochondrial phenotype. Thus, the fragmented ratio can reflect tumor progression that predicts prognosis and therapeutic response. In addition, we investigate whether the targeting of the mitochondrial fission protein Drp1 could be a novel therapeutic approach.

Ferroptosis in Cancer Cell Biology

“…However, this process comes at a cost of ROS production as a byproduct of OXPHOS [43]. Mitochondria are involved in the execution of various types of regulated cell death such as extrinsic and intrinsic apoptosis and autophagy, thereby playing a central role in tissue homeostasis [44,45]. Interestingly, experimental induction of ferroptosis through pharmacological inhibition of xCT was shown to induce mitochondrial fragmentation, mitochondrial ROS production, loss of the mitochondrial membrane potential (MMP) and ATP depletion [18,42,[46][47][48][49].…”

Live imaging of alterations in cellular morphology and organelles during cornification using an epidermal equivalent model

“…3, suggesting that mitochondrial conditions play a role in preparing for the induction of flattening. Generally, mitochondrial morphology is closely associated with the ability of mitochondria to produce energy, and the balance between mitochondrial fission and fusion is important for the maintenance of mitochondrial quantity and quality 46,47 . Mitochondrial fusion is promoted in cells under conditions of high energy demand, whereas mitochondrial fission and subsequent degradation by autophagy are induced in cells under conditions of low energy demand 48 .…”

“…If mitochondria are injured by these factors, the resultant dysfunctional mitochondria are fragmented and subsequently degraded by autophagy to maintain healthy mitochondrial networks 52 . Moreover, severe mitochondrial damage leads to excessive mitochondrial fission and cell death, such as apoptosis, necrosis, and autophagic cell death 47,51,53,54 . Several reports have indicated the involvement of autophagy in keratinocyte differentiation 10,11 .…”

Porcine Circovirus 2 Induction of ROS Is Responsible for Mitophagy in PK-15 Cells via Activation of Drp1 Phosphorylation

“…The link between PINK1 and Parkin is well established. PINK1 stabilizes dysfunctional mitochondria and recruits Parkin from the cytosol to damaged mitochondria [41]. However, the relationship between Drp1 and PINK1/Parkin remains elusive.…”