About this Research Topic
Mitochondria play a pivotal role in several functional processes in neurons, from biogenesis to cell death, which are co-dependent and interrelated. Mitochondrial dysfunction has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Mitochondrial failure ‒ that is often systemic rather than brain-limited ‒ may arise as a consequence of defects in OXPHOS, calcium cell signaling, and elevated oxidative stress; therefore, a protein quality control system to scavenge reactive oxygen species (ROS) and degrade misfolded or damaged proteins is crucial for the organelle function. Thirteen OXPHOS complex proteins are encoded by the mitochondrial genome (mtDNA). Excessive accumulation of mtDNA mutations result in mitochondrial dysregulation and may significantly increase ROS production, thereby contributing to the pathophysiology of these disorders.
The number and morphological properties of mitochondria (associated with disease states) are regulated by an intricate balance between fusion and fission events, which show reciprocal interactions with mitochondrial transport and mitophagy. Selective autophagy (mitophagy) is an additional quality control mechanism for maintaining a healthy mitochondrial network. Several gene products associated with neurodegenerative diseases are mitochondrial resident proteins or can be translocated into mitochondria. Mutations in these genes may induce impaired mitochondrial function via a mechanism that involves either gain- or loss-of-function.
Moreover, about 99% of mitochondrial proteins are nuclear encoded. They are recognized and imported by specialized translocases of mitochondrial membrane. Functional deficits of the import machinery or chaperones involved in this process, cause impaired import of mitochondrial proteins and may contribute to energy failure and lead to neuronal demise.
In summary, a myriad of factors can result in mitochondrial perturbations. Experimental toxin and genetic models have considerably contributed to the understanding of the role of mitochondria in the pathogenic cascade leading to neurodegeneration, which may represent a primary therapeutic target to prevent or reduce the burden of neurodegenerative diseases.
The number and morphological properties of mitochondria (associated with disease states) are regulated by an intricate balance between fusion and fission events, which show reciprocal interactions with mitochondrial transport and mitophagy. Selective autophagy (mitophagy) is an additional quality control mechanism for maintaining a healthy mitochondrial network. Several gene products associated with neurodegenerative diseases are mitochondrial resident proteins or can be translocated into mitochondria. Mutations in these genes may induce impaired mitochondrial function via a mechanism that involves either gain- or loss-of-function.
Moreover, about 99% of mitochondrial proteins are nuclear encoded. They are recognized and imported by specialized translocases of mitochondrial membrane. Functional deficits of the import machinery or chaperones involved in this process, cause impaired import of mitochondrial proteins and may contribute to energy failure and lead to neuronal demise.
In summary, a myriad of factors can result in mitochondrial perturbations. Experimental toxin and genetic models have considerably contributed to the understanding of the role of mitochondria in the pathogenic cascade leading to neurodegeneration, which may represent a primary therapeutic target to prevent or reduce the burden of neurodegenerative diseases.
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