Mitochondrial dynamics as regulators of cancer biology

Abstract

Mitochondria are dynamic organelles that supply energy required to drive key cellular processes, such as survival, proliferation, and migration. Critical to all of these processes are changes in mitochondrial architecture, a mechanical mechanism encompassing both fusion and fragmentation (fission) of the mitochondrial network. Changes to mitochondrial shape, size, and localization occur in a regulated manner in order to maintain energy and metabolic homeostasis, while deregulation of mitochondrial dynamics is associated with the onset of metabolic dysfunction and disease. In cancers, oncogenic signals that drive excessive proliferation, increase intracellular stress, and limit nutrient supply are all able to alter the bioenergetic and biosynthetic requirements of cancer cells. Consequently, mitochondrial function and shape rapidly adapt to these hostile conditions in order to support cancer cell proliferation and evade activation of cell death programs. In this review we will discuss the molecular mechanisms governing mitochondrial dynamics and integrate recent insights into how changes in mitochondrial shape affect cellular migration, differentiation, apoptosis, and opportunities for the development of novel targeted cancer therapies.

Mitochondrial network structure homeostasis and cell death

“…In fact, cancer cells frequently show an imbalance of fission and fusion. Accumulating evidence is beginning to provide an increased mechanistic understanding of how mitochondrial dynamics, which reflect the organelles’ exquisite heterogeneity in shape and spatial distribution, affect tumorigenesis and participate in metabolic reprogramming . Consistent with these observations, many studies have shown that the mitochondria‐associated fission protein Drp1 promotes tumor migration and pathogenesis, including in lung cancer, metastatic breast cancer, glioblastoma, colorectal cancer, pancreatic cancers, thyroid tumors, nasopharyngeal carcinoma and melanoma (Table ).…”

T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression

“…The inner mitochondrial membrane is extensively folded, producing invaginations called cristae, which control oxidative phosphorylation (OXPHOS), electron and metabolite transport, and cell death and survival (3). Consequently, mitochondrial network dysregulation is linked to several pathophysiological conditions, including cancer, diabetes, and neurodegenerative diseases (4)(5)(6)(7)(8).…”

“…Conversely, mitochondrial dynamics is controlled by mitochondrion-shaping proteins that regulate fusion and fission events. Core components of the mitochondrial fusion/ fission machinery include mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1), which promote fusion, whereas fission is governed by dynamin-related protein 1 (DRP1) and by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins (MiD49 and MiD51), and fission 1 (FIS1) (1)(2)(3)(4)(5)(6)(7)(8).…”

Tuning the Hydrophobicity of a Mitochondria‐Targeted NO Photodonor

“…Although most solid tumors obtain their energy from aerobic glycolysis (Warburg effect), mitochondria still play a key role in tumor growth . Active mitochondria favor tumorigenesis, cell migration, metastasis and drug resistance .…”

“…Active mitochondria favor tumorigenesis, cell migration, metastasis and drug resistance . By contrast, impairing oxidative phosphorylation in mitochondria decreases cancer cell proliferation and invasion, and triggers apoptosis . Cancer cell mitochondria have higher transmembrane potentials than non‐transformed cells .…”