Clinical Approaches for Mitochondrial Diseases

Abstract

Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform 'oxidative phosphorylation (OX PHOS)', which are expressed by the mitochondria's self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.

Keywords: clinical trials; mitochondrial diseases; mitochondrial therapy.

Figure 1

Symptoms and causes of mitochondrial diseases. The upper side of the figure displays commonly diagnosed symptoms, with symptoms affecting the entire body placed on the left and organ-specific symptoms on the right. As mitochondrial diseases have various causes, only well-known pathogenic mtDNA mutations are listed. A line and brief illustration indicate a correlation between pathogenic mutations and the affected sites. Details can be found in Table 1, Section 3.

Figure 2

Interactions of treatments for mitochondrial diseases. Targeting points of drugs are indicated with arrows with brief illustrations. The treatments are displayed using their known names and features, and further detailed mechanisms for each treatment can be found in Section 4 and Section 5 and Table 2 and Table 3.

Figure 3

Currently developed mitochondrial base editor. Identical proteins are displayed with the same shape and color. Target and edited nucleotides are marked using boxes, with the edited nucleotides shown in orange. An arrow indicates another form of the same base editor with different deaminase activity. Further details can be found in Section 6.