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Genetic features of mitochondrial respiratory chain disorders
1INSERM U393 and Service de Génétique, Hôpital Necker-Enfants Malades, Paris, France. roetig@necker.fr
Insights
Respiratory chain (RC) deficiencies, crucial for ATP synthesis, can cause diverse symptoms due to genetic origins in both nuclear and mitochondrial DNA. Research increasingly identifies nuclear gene mutations as a cause of these energy metabolism disorders.
Area of Science:
- Biochemistry
- Genetics
- Cellular Respiration
Background:
- Oxidative phosphorylation generates ATP via the oxygen-consuming respiratory chain (RC), essential for energy supply in most tissues.
- RC disorders can manifest with varied symptoms across organs, ages, and inheritance patterns due to dual genetic origins (nuclear and mitochondrial DNA).
- Historically, mitochondrial DNA mutations were primarily linked to RC disorders, but nuclear gene involvement is increasingly recognized.
Purpose of the Study:
- To highlight the genetic complexity of respiratory chain disorders.
- To emphasize the growing understanding of nuclear gene contributions to RC deficiencies.
- To underscore the broad clinical spectrum and etiological diversity of these conditions.
Main Methods:
- Review of current literature on respiratory chain disorders.
- Analysis of genetic bases, including mitochondrial and nuclear DNA mutations.
- Correlation of genetic findings with clinical manifestations.
Main Results:
- Respiratory chain deficiencies can present with any symptom, in any organ, at any age, and with any inheritance pattern.
- While mitochondrial DNA mutations were initially the focus, a growing number of nuclear gene mutations are identified as causative.
- Nuclear genes encode RC subunits, biogenesis factors, and mitochondrial DNA metabolism enzymes.
Conclusions:
- Respiratory chain disorders have a complex genetic etiology involving both mitochondrial and nuclear genomes.
- The diagnostic landscape for RC deficiencies is expanding with the identification of nuclear gene defects.
- Understanding the dual genetic origin is critical for accurate diagnosis and management of these energy metabolism disorders.
Abstract:
Oxidative phosphorylation, i.e., ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, being functional before birth. Consequently, RC deficiencies can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, because of the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It was long wrongly considered that RC disorders originate from mutations of mitochondrial DNA, because for a long time only mutations or deletions of mitochondrial DNA were identified. However, the number of known disease-causing mutations in nuclear genes is steadily growing. These genes encode the various subunits of each complex, ancillary proteins functioning at different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups, and protein assembly, and various enzymes involved in mitochondrial DNA metabolism.