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Review
. 2021 Aug 11:12:693734.
doi: 10.3389/fphys.2021.693734. eCollection 2021.

Leigh Syndrome: A Tale of Two Genomes

Ajibola B Bakare  1 , Edward J Lesnefsky  2   3   4 , Shilpa Iyer  1
Affiliations
Review

Leigh Syndrome: A Tale of Two Genomes

Ajibola B Bakare et al. Front Physiol. .

Abstract

Leigh syndrome is a rare, complex, and incurable early onset (typically infant or early childhood) mitochondrial disorder with both phenotypic and genetic heterogeneity. The heterogeneous nature of this disorder, based in part on the complexity of mitochondrial genetics, and the significant interactions between the nuclear and mitochondrial genomes has made it particularly challenging to research and develop therapies. This review article discusses some of the advances that have been made in the field to date. While the prognosis is poor with no current substantial treatment options, multiple studies are underway to understand the etiology, pathogenesis, and pathophysiology of Leigh syndrome. With advances in available research tools leading to a better understanding of the mitochondria in health and disease, there is hope for novel treatment options in the future.

Keywords: Leigh syndrome; mitochondria; mitochondrial DNA; mitochondrial genetics; respiratory chain complex.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The mitochondrial electron transport chain. The subunits of the respiratory chain are encoded by nDNA and mtDNA. Mitochondria produce ATP via the OXPHOS pathway; a process that takes place at the inner mitochondrial membrane involves the channeling of electrons through four-electron transport chain (ETC) complexes (Complex I–IV). The electron transport results in subsequent translocation of protons from the matrix into the intermembrane space, this proton gradient in combination with the inward-negative mitochondrial membrane potential drives the molecular motor, ATP synthase (complex V), to produce ATP. An impairment in the ETC or its assembly complexes results in metabolic malfunction in cells and tissues. The ETC is a vast complex comprising ∼90 different subunits which make up the five enzyme complexes of OXPHOS. Of these subunits, mtDNA encodes 13 subunits while the nuclear DNA (nDNA) encodes ∼77 subunits. Together, the nDNA and mtDNA coordinate the synthesis of subunits that come together to form the individual complexes that compose the ETC, subsequently allowing the mitochondria to function as the core energy producer for cellular needs. Specific genes encoded by nDNA and mtDNA in the context of LS are listed.
FIGURE 2
FIGURE 2
Clinical features of Leigh syndrome. Figure showing the various clinical features associated with LS. The most prevalent clinical features affect the brain, muscles, and eyes. Other clinical findings include dysfunctions in cardiovascular, gastrointestinal, renal, auditory, and hematological systems. LS can present as early onset or late-onset with abnormalities in at least 3 of the organ systems highlighted. LS results from pathogenic mutations in either the nDNA or mtDNA that causes abnormalities in the OXPHOS capacities of the mitochondria. Hence, biochemical findings reflect these defects.
See this image and copyright information in PMC

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