Recent advances in mitochondrial diseases: From molecular insights to therapeutic perspectives

Abstract

Mitochondria are double-membraned cytoplasmic organelles that are responsible for the production of energy in eukaryotic cells. The process is completed through oxidative phosphorylation (OXPHOS) by the respiratory chain (RC) in mitochondria. Thousands of mitochondria may be present in each cell, depending on the function of that cell. Primary mitochondria disorder (PMD) is a clinically heterogeneous disease associated with germline mutations in mitochondrial DNA (mtDNA) and/or nuclear DNA (nDNA) genes, and impairs mitochondrial structure and function. Mitochondrial dysfunction can be detected in early childhood and may be severe, progressive and often multi-systemic, involving a wide range of organs. Understanding epigenetic factors and pathways mutations can help pave the way for developing an effective cure. However, the lack of information about the disease (including age of onset, symptoms, clinical phenotype, morbidity and mortality), the limits of current preclinical models and the wide range of phenotypic presentations hamper the development of effective medicines. Although new therapeutic approaches have been introduced with encouraging preclinical and clinical outcomes, there is no definitive cure for PMD. This review highlights recent advances, particularly in children, in terms of etiology, pathophysiology, clinical diagnosis, molecular pathways and epigenetic alterations. Current therapeutic approaches, future advances and proposed new therapeutic plans will also be discussed.

Keywords: Epigenetic alterations; Fetal gene therapy; Gene editing; Mitochondrial diseases; Nanomedicine.

Fig. 1

Human mitochondrial DNA. The human mitochondrial genome is organized as double-stranded a light (inner) and a heavy (outer) circular molecule containing 37 genes. 13 of these genes encode one polypeptide subunit, which is involved in the regulation of respiratory chain (RC), while the remaining 24 are necessary for RNA translation mechanism, 2 for making molecules called ribosomal RNAs (rRNAs) and 22 for transfer RNAs (tRNAs). Created with Biorender.com.

Fig. 2

Schematic presentation of homoplasmic and heteroplasmic mitochondrial DNA. A single cell may obtain wild type copies of mtDNA (homoplasmy) or a mixture of mutant and wild-type mtDNA (heteroplasmy)). The proportion of mutant mtDNA copies determines the penetrance and severity of phenotype expression, and the cell will be affected if it exceeds a specific limit (threshold). Abbreviations: mtDNA, mitochondrial DNA. Created with Biorender.com.

Fig. 3

Schematic presentation of clinical features of mitochondrial diseases. The clinical features of mitochondrial diseases vary between patients and have non-neurological or neurological characteristics, commonly involving two or more organ systems causing dysfunction of any organ or tissue. Created with Biorender.com.

Fig. 4

Clinical presentation of childhood-onset mitochondrial diseases. Genotypic and phenotypic features of mitochondrial diseases in children. Abbreviations: ASH, Alpers–Huttenlocher syndrome; myopathy sensory ataxia; ANS, Ataxia neuropathy spectrum; CLA, Congenital lactic acidosis. Created with Biorender.com.