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Mitochondrial Complex III Deficiency of Nuclear Origin:

Molecular Basis, Pathophysiological Mechanisms, and Mouse Models

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Mitochondrial Disorders Caused by Nuclear Genes

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Abstract

Mitochondrial respiratory chain complex III enzyme deficiency is associated with a heterogeneous group of neuromuscular and multisystemic disorders of variable severity that are present in childhood and adulthood. Despite being considered a relatively uncommon defect of the OXPHOS system, interest has recently shifted toward the Mendelian inheritance of mitochondrial complex III-related disease due to the increasing number of nuclear genetic defects that affect its biogenesis and function. Not only are most complex III subunits encoded by nuclear genes, but also are an increasing number of specific regulatory proteins and assembly factors involved in the biosynthesis of this respiratory chain complex, which have been described in different organisms. From a clinic-genetic point of view, inherited complex III enzyme deficiency can be classified into disorders due to mutations in complex III structural constituents, or those caused by mutations in assembly chaperones, such as BCS1L and TTC19. The first part of this review will focus on the relationships between the nuclear genetic alterations that lead to complex III deficiency and their clinical manifestations. The second part will explain what is known so far about the cellular pathophysiological consequences of complex III dysfunction with regards to defects in the activity and assembly of the respirasome, and the alterations in the production of reactive oxygen species and mitochondrial dynamics. The final part of this review will describe the development and experimental advances in new mammalian models of complex III deficiency with a special emphasis on the GRACILE mouse, which has arisen as a powerful approach to better understand complex III enzyme deficiency of nuclear origin.

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Acknowledgments

This study was supported by Instituto de Investigación Hospital Universitario 12 de Octubre (I+12), and Instituto de Salud Carlos III (ISCIII)/Ministry of Science and Innovation (MCINN) to C.U. (grant numbers PI08-0021 and PI11-00182), to M.M. (CP11-00151) and to M.A.M. (PI09-01359). M.A.M. was the recipient of a “Intensificación de la Actividad Investigadora” action from ISCIII and Comunidad Autónoma de Madrid (CAM), Spain.

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  1. Instituto de Investigación, Hospital Universitario 12 de Octubre, Avda. de Córdoba s/n, 28041, Madrid, Spain

    Alberto Blázquez M.Sc., Lorena Marín-Buera M.Sc., María Morán Ph.D., Alberto García-Bartolomé, Joaquín Arenas Ph.D., Miguel A. Martín Ph.D. & Cristina Ugalde Ph.D.

  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010, Valencia, Spain

    Alberto Blázquez M.Sc., Lorena Marín-Buera M.Sc., María Morán Ph.D., Alberto García-Bartolomé, Miguel A. Martín Ph.D. & Cristina Ugalde Ph.D.

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  1. , Dept. of Molecular and Human Genetics, Baylor College of Medicine, Baylor Plaza ONE, Houston, 77030, Texas, USA

    Lee-Jun C. Wong

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Blázquez, A. et al. (2013). Mitochondrial Complex III Deficiency of Nuclear Origin:. In: Wong, LJ. (eds) Mitochondrial Disorders Caused by Nuclear Genes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3722-2_14

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