Understanding metabolic and stress changes in mitochondrial disease. A case study in Leber’s Hereditary Optic Neuropathy

Abstract

Mitochondria are organelles which perform various roles in the cell (mainly the energy production) and house their own genetic material, the mitochondrial DNA. Mutations in this genome and/or genes of the nuclear DNA affecting mitochondrial function are the cause of a set of rare pathologies (1 patient:5000 individuals) known as mitochondrial diseases (MDs).MDs comprise a wide range of disorders with high phenotypic variability and unknown molecular mechanisms, which limits their diagnosis and treatment. Recently, multi-omic approaches have emerged as a possible tool to identify new biomarkers and pathways involved in these pathologies pointing to fundamental metabolic routes such as the mechanistic target of rapamycin complex 1, the Integrated Stress Response and the Activating Transcription Factor 4. Here, we present a comprehensive review of the latest insights in the field, compiling recent publications on metabolomics as well as transcriptomic data trying to dissect the puzzle underlying the complexity MDs. In addition, we perform a case study on cell lines carrying two primary mutations causing Leber’s Hereditary Optic Neuropathy to investigate how different elements of cellular stress are altered in this disease.Interestingly, we find a mutation-specific response which might be related to the severity of the variant.