Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential

Abstract

Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increasing evidence suggests that mtDNA mutations, mtDNA epigenetics and miRNA regulations dynamically modify signalling pathways in an altered microenvironment, resulting in cancer initiation and progression and aberrant therapy response. In this review, we discuss mitochondria as organelles importantly involved in tumorigenesis and anti-cancer therapy response. Tumour treatment unresponsiveness still represents a serious drawback in current drug therapies. Therefore, studying aspects related to genetic and epigenetic control of mitochondria can open a new field for understanding cancer therapy response. The urgency of finding new therapeutic regimens with better treatment outcomes underlines the targeting of mitochondria as a suitable candidate with new therapeutic potential. Understanding the role of mitochondria and their regulation in cancer development, progression and treatment is essential for the development of new safe and effective mitochondria-based therapeutic regimens.

Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

“…Mitochondria also regulate SAM-mediated DNA methylation patterns pivotal to numerous signaling pathways through epigenetic events. Consistent with mitochondria-mediated epigenetic regulation, the clinical presentation of bioenergetics diseases simulates epigenetic pathologies, which also include cancer [119,120]. Thus, exploring the bioenergetics-epigenetic interface may also prove a logical approach to harness successful cancer treatment modalities.…”

Integrating mitoepigenetics into research in mood disorders: a state-of-the-art review

“…MitomiRs have been demonstrated to be important regulators of mitochondrial function ( Rencelj et al, 2021 ). The regulation of mitochondria by mitomiRs influences the development of numerous diseases caused by mitochondrial dysfunction, contributing to the pathophysiology of conditions such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancers ( Dong et al, 2020 ; Wagner et al, 2022 ).…”

Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy

“…It has also been observed that mtDNA content is reduced in tumor‐initiating cells, which are thought to play a role in cancer recurrence after chemotherapy 18 . Cancer cells often have mutations in mtDNA, but these mutations do not completely impair the mitochondria‐mediated energy metabolism and functionality 19 . Rather than that, these mutations promote alteration of the biosynthetic and bioenergetic characteristics of the cancerous cell via mitochondria‐to‐nucleus signaling.…”

“… 18 Cancer cells often have mutations in mtDNA, but these mutations do not completely impair the mitochondria‐mediated energy metabolism and functionality. 19 Rather than that, these mutations promote alteration of the biosynthetic and bioenergetic characteristics of the cancerous cell via mitochondria‐to‐nucleus signaling. This signaling pathway is activated by “dysfunctional” mitochondria that lead to mitophagy and alter the activity and/or transcription of cancer‐related genes and signaling pathway.…”