Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain

Abstract

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as ‘mitoexome’, ‘mitoproteome’ and ‘mitointeractome’ have entered the field of ‘mitochondrial medicine’. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

“…Another important factor that may influence Nrf2 alterations seen in IMDs is whether the patients have a residual activity of the deficient enzyme, or it is null. Noteworthy, the degree of enzymatic activity often correlates with the disease phenotype (e.g., higher enzyme activity usually causes milder phenotypes) ( Gieselmann, 2005 ; Oliveira and Ferreira, 2019 ; Grünert et al, 2021 ; Zanfardino et al, 2021 ). As for FRDA, it should be highlighted that the content of frataxin may influence Nrf2 activation.…”

Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse

“…Among them, complex I deficiency accounts for ~30% of MD’s diagnosed cases, and it is considered the most frequent cause of these disorders [ 3 , 4 , 5 ]. The tissues most affected by mitochondrial dysfunction are those with higher oxygen and energy demands, such as nervous tissue, muscle, heart and liver tissues [ 1 , 6 , 7 ]. Particularly, the nervous system energy requirements are higher than any other tissue or organ [ 8 , 9 , 10 ], and neuronal function relies on OXPHOS activity for processes such as ion transport, synaptic trafficking, vesicle release and neurotransmitter recycling [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Nuclear genome-encoded mitochondrial OXPHOS complex I genes in Buffalo show tissue-specific differences

“…According to Lax et al [21], any mutation in the nuclear or mitochondrial genome can result in defective mitochondrial functionality, resulting in varying levels of oxidative responses that can affect various organs and tissue types in accordance with the extent of the defect and stress. Any defect in nuclear-encoded mitochondrial protein (NuMP) genes at the cellular level affects OXPHOS activities, mtDNA maintenance, mitochondrial import, mitochondrial protein synthesis, iron homeostasis, coenzyme q10 biogenesis, mitochondrial quality control, its integrity, mitochondrial metabolism and is also responsible for metabolic and de ciency diseases such as early embryonic lethality and mitochondrial encephalopathy [22][23][24][25]. Moreover, genetic variations in NuMP genes associated with complex I lead to an assortment of de ciency diseases and clinical anomalies, such as Leigh syndrome, lactic acidosis and stroke-like episodes (MEALS), Leber's hereditary optic neuropathy, and Parkinson's disease.…”