Mitochondrial Control of Genomic Instability in Cancer

Abstract

Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. Interestingly, a relatively poorly explored aspect of mitochondria in neoplastic disease is their contribution to the characteristic genomic instability that underlies the evolution of the disease. In this review, we summarize the known mechanisms by which mitochondrial alterations in cancer tolerate and support the accumulation of DNA mutations which leads to genomic instability. We describe recent studies elucidating mitochondrial responses to DNA damage as well as the direct contribution of mitochondria to favor the accumulation of DNA alterations.

A Novel Mitochondrial-Related Nuclear Gene Signature Predicts Overall Survival of Lung Adenocarcinoma Patients

“…Mitochondria are complex organelles of bioenergetic, biosynthetic, and signaling that are correlated to several diseases, including cardiovascular diseases, neurological disorders, and metabolism disorders ( Vyas et al, 2016 ; Genovese et al, 2020 ). In addition, recently, mitochondria are demonstrated to participate in multiple aspects of tumor formation and progression ( Hsu et al, 2016 ; Bonora et al, 2021 ). The mechanisms of mitochondria involved in tumorigenesis have been extensively studied ( Nunes et al, 2015 ), and some specific nuclear mitochondrial genes (NMGs) were regarded as the potential targets for the development of the next generation of cancer therapeutics ( Su et al, 2016 ; Zong et al, 2016 ).…”

Targeted Anti-Mitochondrial Therapy: The Future of Oncology

“…Genomic instability is a hallmark of cancer, and mitochondria can assist genomic instability in several ways. First, elevated mtROS directly damage mitochondrial and nuclear DNA by oxidizing nucleosides [ 76 ]. Another mechanism by which mitochondria lead to DNA mutation is by inducing minority mitochondrial outer membrane permeabilization (MOMP).…”

Epigenetic Regulation: A Link between Inflammation and Carcinogenesis

“…Moreover, during aging, this fine-tuned mechanism becomes progressively unbalanced, suggesting that aging cells could represent a favorable environment, which, if hit by protumoral mutations, can more easily move toward carcinogenesis [ 19 ]. For example, abnormal hypermethylation of the MutL homologus 1 ( MLH1) promoter, a gene involved in hereditary nonpolyposis colorectal cancer has been related to gene silencing and microsatellite instability, which in turn could initiate genetic instability in colorectal and endometrial cancers [ 20 , 21 , 22 , 23 ]. Interestingly, most large bowel adenocarcinomas with MLH1 methylation display widespread methylation of the promoter of several genes, the so-called CIMP phenotype, and the BRAF-V600E mutation.…”