Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy

Abstract

Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.

Keywords: cancer radioresistance; clinically relevant radioresistant (CRR) cells; mitochondria; mitochondrial DNA.

Figure 1

Mitochondrial DNA (mtDNA) mutations that cause various diseases, as well as mtDNA mutations that affect longevity or radioresistance. Centenarian: a person over 100 years old; MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; CPEO: chronic progressive external ophthalmoplegia; DM: diabetes mellitus; LHON: Leber’s hereditary optic neuropathy; AD/PD: Alzheimer’s and Parkinson’s diseases; MERRF: myoclonic epilepsy and ragged red fibers; LS: Leigh syndrome; NARP: neuropathy, ataxia, and retinitis pigmentosa; RS: radiosensitive; RR: radioresistance; MM: mitochondrial myopathies; EXIT: exercise intolerance.

Figure 2

Morphology of CRR cells, ρ⁰ cells, ρ⁰ cells harboring transferred mitochondria, and parental cells. (A): HeLa parent cells, (B): HeLa CRR cells, (C): HeLa ρ⁰ cells, (D): HeLa ρ⁰ Mito cells, (E): SAS parent cells, (F): SAS CRR cells, (G): SAS ρ⁰ cells, (H): SAS ρ⁰ Mito cells.

Figure 3

Mitochondria transplantation (mtTP) is a candidate strategy designed to rescue mitochondrial quality control failure. Mitochondrial dysfunction induced by mtDNA mutation or a decrease in mtDNA copy number leads to a decrease in ATP production, a decrease in mitochondrial membrane potential (ΔΨm), and opening of the mitochondrial membrane permeable transition pore (mPTP). This mitochondrial quality control failure induces treatment resistance and mitochondrial disease. Mitochondrial quality control failure may be rescued by transplantation of healthy mitochondria.