Mitochondrial dynamics and oxidative phosphorylation as critical targets in cancer

Abstract

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional and the full range of mechanistic inter-connections are still being unraveled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

Mitochondrial Dysfunction by FADDosome Promotes Gastric Mucosal Injury in Portal Hypertensive Gastropathy

“…Mitochondrial dynamics might play an essential role in stress signaling 34 . Increased RIPK1 and Drp1 expression rather than RIPK3 expression was found in the gastric mucosal samples of mice with PVL and PHG patients compared with that in the corresponding control groups, and the upregulation of RIPK1 and Drp1 in mice with PVL was reversed by IFX treatment ( Figure 3 A, 3B ).…”

The role of mitochondrial dynamics in disease

“…252,253 Excessive mitochondrial fission plays a causal role in promoting cancer cell transformation. 254 Many tumors exhibit fragmented mitochondria with upregulated DRP1 and decreased expression levels of MFN1 and MFN2 255 in ovarian cancer, 256 HCC, 257 lung cancer, 258 colon cancer, 259 breast cancer, 252 neuroblastoma, 260 and glioblastoma, 253 Proliferation and metastasis Combination of with generic autophagy inhibitor hydroxychloroquine with trametinib significantly reduced pancreatic ductal adenocarcinoma (PDAC) tumor burden 293,294 The overexpression of Parkin and PINK1 in breast and glioma cells attenuates cellular proliferation…”

“…In most cases, mitochondrial fission facilitates the cancer cell proliferation, migration, and drug resistance, causing cancer development 252,253 . Excessive mitochondrial fission plays a causal role in promoting cancer cell transformation 254 . Many tumors exhibit fragmented mitochondria with upregulated DRP1 and decreased expression levels of MFN1 and MFN2 255 in ovarian cancer, 256 HCC, 257 lung cancer, 258 colon cancer, 259 breast cancer, 252 neuroblastoma, 260 and glioblastoma, 253 which are correlated to the metastatic potential of cancer cells.…”

“… 252 , 253 Excessive mitochondrial fission plays a causal role in promoting cancer cell transformation. 254 Many tumors exhibit fragmented mitochondria with upregulated DRP1 and decreased expression levels of MFN1 and MFN2 255 in ovarian cancer, 256 HCC, 257 lung cancer, 258 colon cancer, 259 breast cancer, 252 neuroblastoma, 260 and glioblastoma, 253 which are correlated to the metastatic potential of cancer cells. Increased DRP1 or DRP1‐Ser616 phosphorylation levels can prevent apoptosis, change cellular metabolism, induce immune escape, sustain cell cycle and proliferation in tumor cells, and ultimately promote the occurrence and development of tumors.…”

Mitochondrial oxidative phosphorylation and dynamics in mouse liver infected with Plasmodium berghei and the modulatory effects of a novel compound purified from Phyllanthus amarus

“…Mitochondrial dynamics and oxidative phosphorylation are interconnected. Because mitochondrial fusion has been found to support increased oxidative phosphorylation (Yao et al, 2019;Punter et al, 2022). It is strongly believed also that Plasmodium infection causes bioenergetics stress in the host while intervention by treating the infection with different drugs may elicit multivariable effects.…”