Systems Biology Approaches Toward Understanding Primary Mitochondrial Diseases

Primary mitochondrial diseases form one of the most common and severe groups of genetic disease, with a birth prevalence of at least 1 in 5000. These disorders are multi-genic and multi-phenotypic (even within the same gene defect) and span the entire age range from prenatal to late adult onset. Mitochondrial disease typically affects one or multiple high-energy demanding organs, and is frequently fatal in early life. Unfortunately, to date there are no known curative therapies, mostly owing to the rarity and heterogeneity of individual mitochondrial diseases, leading to diagnostic odysseys and difficulties in clinical trial design. This review aims to discuss recent advances and challenges of systems approaches for the study of primary mitochondrial diseases. Although there has been an explosion in the generation of omics data, few studies have progressed toward the integration of multiple levels of omics. It is evident that the integration of different types of data to create a more complete representation of biology remains challenging, perhaps due to the scarcity of available integrative tools and the complexity inherent in their use. In addition, "bottom-up" systems approaches have been adopted for use in the iterative cycle of systems biology: from data generation to model prediction and validation. Primary mitochondrial diseases, owing to their complex nature, will most likely benefit from a multidisciplinary approach encompassing clinical, molecular and computational studies integrated together by systems biology to elucidate underlying pathomechanisms for better diagnostics and therapeutic discovery. Just as next generation sequencing has rapidly increased diagnostic rates from approximately 5% up to 60% over two decades, more recent advancing technologies are encouraging; the generation of multi-omics, the integration of multiple types of data, and the ability to predict perturbations will, ultimately, be translated into improved patient care.