Abstract
This review presents our current understanding of the pathophysiology and potential treatment strategies with respect to mitochondrial disease in children. We focus on pathologies due to mutations in nuclear DNA‐encoded structural and assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system, with a particular emphasis on isolated mitochondrial complex I deficiency. Following a brief introduction into mitochondrial disease and OXPHOS function, an overview is provided of the diagnostic process in children with mitochondrial disorders. This includes the impact of whole‐exome sequencing and relevance of cellular complementation studies. Next, we briefly present how OXPHOS mutations can affect cellular parameters, primarily based on studies in patient‐derived fibroblasts, and how this information can be used for the rational design of small‐molecule treatment strategies. Finally, we discuss clinical trial design and provide an overview of small molecules that are currently being developed for treatment of mitochondrial disease.
Highlights
Mitochondria are semi-autonomous organelles that are present in the cytosol of virtually all cells
We primarily focus on mitochondrial diseases that (i) clinically manifest themselves before the age of 18 years and (ii) arise from mutations in nuclear DNA-encoded structural proteins or assembly factors of the mitochondrial oxidative phosphorylation (OXPHOS) system
The mitochondrial OXPHOS system is embedded in the mitochondrial inner membrane (MIM) and represents the final step in the conversion of nutrients to energy by catalyzing the generation of ATP (Fig 1A)
Summary
Mitochondria are semi-autonomous organelles that are present in the cytosol of virtually all cells. ADME, absorption, distribution, metabolism, and excretion; API, active pharmacological ingredient; BBB, blood–brain barrier; CMC, chemistry and manufacturing controls; CTA, clinical trial application; GLP, good laboratory practices; GMP, good manufacturing practices; CYP, cytochrome P450; IB, investigational brochure; ICH, The International Conference on Harmonisation (of Technical Requirements for Registration of Pharmaceuticals for Human Use); IMPD, investigational medical product dossier; IND, investigational new drug; N.a., not appropriate; PD, pharmacodynamics; PK, pharmacokinetics; PPB, plasma protein binding; UGT, UDP glucuronosyltransferase.
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