Kearns–Sayre syndrome and large-scale mitochondrial DNA deletion disorders

Background: Mitochondrial diseases are a group of rare disorders caused by alterations in mitochondrial DNA (mtDNA). Kearns–Sayre syndrome is characterized by a large-scale mtDNA deletion that impairs the synthesis of respiratory chain components, leading to cellular energy depletion and oxidative stress. Objective: To summarize current data on the molecular genetic and biochemical mechanisms underlying mitochondrial diseases using Kearns–Sayre syndrome as a model, describe its clinical and diagnostic criteria, and consider promising experimental approaches to targeted therapy. Methods: Scientific sources from the PubMed database were analyzed using key search terms: Kearns–Sayre syndrome, mitochondrial diseases, chronic progressive external ophthalmoplegia, pigmentary retinopathy, electron transport chain deficiency, and mitochondrial DNA deletion. The primary selection encompassed publications from 2022 to 2026; however, to provide a comprehensive coverage of the topic, selected relevant foundational sources from earlier years were also included. Results: To review relevant scientific publications was conducted, focusing on the molecular basis of large-scale mtDNA deletions, mechanisms of heteroplasmy, diagnostic algorithms, and novel therapeutic modalities for mitochondrial disorders. It is stated that impairment of the mitochondrial respiratory chain (MRC), specifically complexes I and IV, triggers oxidative stress due to reactive oxygen species accumulation, a metabolic shift toward anaerobic glycolysis with energy depletion, and lactic acidosis, collectively underlying the characteristic clinical triad. Diagnostics relies on a combination of long-range PCR and next-generation sequencing (NGS) of mtDNA from peripheral blood or muscle biopsies to detect low levels of hete­roplasmy. Symptomatic management remains the primary approach, however, experimental mitochondrial genome-editing methods show promise for selectively reducing mutant mtDNA levels and restoring MRC functional activity and oxidative phosphorylation. Conclusions: Mitochondrial diseases are severe multisystem disorders for which timely molecular diagno­stics, multidisciplinary surveillance, and the further development of targeted mitochondrial DNA editing­ technologies are of paramount importance.