Mitochondrial Neurodegeneration

Abstract

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as ‘mitochondrial medicine’.

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“…MDs are long-term, genetic disorders characterized by alterations in mitochondrial function that may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins or non-protein-coding RNA [ 6 , 7 ].…”

How to mitigate neurological and cardiac decompensation in Leigh syndrome: Can nicotinamide riboside be an answer?

“…The first important finding of Yoon and colleagues is the demonstration that NDUFS4‐related complex I deficiency leads to severe bradyarrhythmia and sinoatrial nodal dysfunction. LS is known to cause neurological defects, with pathognomonic symmetric lesions in the central nervous system 4 . However, other clinical findings have also been associated with LS, including hepatic, gastrointestinal and cardiac dysfunction 5 .…”

AIFM1 beyond cell death: An overview of this OXPHOS-inducing factor in mitochondrial diseases

“… 1 , 2 , 3 , 4 Given the critical role of mitochondria in both catabolic and anabolic processes, it should come as no surprise that lesions of mitochondrial components and/or proteins involved in mitochondrial bioenergetics can lead to human diseases. 5 , 6 The impact of mitochondrial dysfunction is not restricted to inherited metabolic syndromes, 7 , 8 but rather extends to age-related frailty, tumorigenesis, cardiovascular, metabolic and neurodegenerative diseases. 9 , 10 , 11 , 12 , 13 For the large majority of human illnesses with clear signatures of mitochondrial dysfunction, patients may develop a variety of symptoms with variable age-onset, organ involvement and clinical outcomes that negatively impact their life quality and may shorten their lifespan expectancy.…”