Mitochondrial disorders

Abstract

Mitochondria, double-membrane organelles, are the major site of energy production and vital components of all eukaryotic cells because of the presence in their inner membrane of the respiratory chain (RC) which accomplishes oxidative phosphorylation (OXPHOS). In addition to respiration, mitochondria carry out diverse tasks which include import of proteins, ions, and metabolites, anaplerotic and degradative metabolic reactions, organelle dynamics, and signaling for apoptosis. Despite this multiplicity of functions, the term “mitochondrial disorders” is currently ascribed to OXPHOS diseases. Given the complexity of its biochemistry and of its peculiar dual genetic control, proper OXPHOS is a process that requires the assembly of numerous different proteins coded either by the mitochondrial genome or by the nuclear genome, and the orchestrated function of the five respiratory chain enzyme complexes packaged in the RC, the special hetero-multimeric structure of the inner mitochondrial membrane. Hence, mutations in mitochondrial DNA genes or in nuclear DNA genes encoding integral proteins of the RC subcomplexes, their regulatory and assembly factors, and the set of proteins that complete and regulate cellular bioenergetics, cause OXPHOS dysfunction and a corresponding variety of genetic diseases with heterogeneous clinical manifestations. This chapter focuses on mitochondrial disorders that express significant pathology in the cerebellum and in its long-tract connections with the peripheral organs, particularly the neuromuscular and osteoarticular systems, and manifest with spinocerebellar Ataxia as the prominent symptom or sign.