Mitochondrial Disease: Advances in Clinical Diagnosis, Management, Therapeutic Development, and Preventative Strategies

Abstract

Purpose of review Primary mitochondrial disease encompasses an impressive range of inherited energy deficiency disorders having highly variable molecular etiologies as well as clinical onset, severity, progression, and response to therapies of multi-system manifestations. Significant progress has been made in primary mitochondrial disease diagnostic approaches, clinical management, therapeutic options, and preventative strategies that are tailored to major mitochondrial disease phenotypes and subclasses. Recent findings The extensive phenotypic pleiotropy of individual mitochondrial diseases from an organ-based perspective is reviewed. Improved consensus on standards for mitochondrial disease patient care are being complemented by emerging therapies that target specific molecular subtypes of mitochondrial disease. Reproductive counseling options now include preimplantation genetic diagnosis at the time of in vitro fertilization for familial mutations in nuclear genes and some mtDNA disorders. Mitochondrial replacement technologies have promise for some mtDNA disorders, although practical and societal challenges remain to allow their further research analyses and clinical utilization. Summary A dramatic increase has occurred in recent years in the recognition, understanding, treatment options, and preventative strategies for primary mitochondrial disease.

Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

“…mtDNA mutation analysis is complicated by heteroplasmy, which is the ratio of the number of copies of a mutated mtDNA genome to all mtDNA genomes in a cell or tissue (8,9). The high mtDNA coverage achieved in the next generation sequencing (NGS) data allowed us to accurately assess low-level heteroplasmy, measured as variant allele frequency (VAF), and minimize potential contamination of non-mtDNA genome reads from contaminating nuclear mtDNA transcripts ("NuMTs"; ref.…”

“…Mitochondrial DNA mutations have a pathogenic role in complex, multisystem disorders affecting nearly every organ at every age (8,9). Despite extensive phenotypic heterogeneity, cancer is not commonly observed in patients with mitochondrial diseases.…”

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein inC. elegans

“…Interestingly, this behavior is very similar to the perceived fatigue often observed in patients with mitochondrial disorders [31] and given the suppressive effect of lutein, it provides us with a very sensitive and quick assay for future suppressor screening. It will be important to further investigate whether complex I deficiency or suppression of other HMAD genes increases sensitivity to metabolic or environmental stressors as these factors may influence mitochondrial activity and have devastating consequence on patients with Leigh Syndrome or other mitochondrial-associated disorders [73,74]. Of note, although we observed increased ROS production in both C. elegans and patients' fibroblasts, accompanied by increased expression of stress response genes (e.i.…”

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction

“…The use of PET imaging is not limited to elucidating the pathogenesis; it can also directly evaluate the effects of therapeutic agents on the pathological targets. In addition to the aforementioned studies in Parkinson's disease and ALS, several clinical trials testing new therapeutic molecules having antioxidant effects, such as vatiquinone (EPI-743) and elamipretide (MTP-131), are ongoing on patients with mitochondrial diseases [181,182]. Oxidative stress imaging is thus also able to assess the therapeutic efficacy of these agents against oxidative stress in living patients.…”