Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation

Abstract

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

A Highly Selective In Vitro JNK3 Inhibitor, FMU200, Restores Mitochondrial Membrane Potential and Reduces Oxidative Stress and Apoptosis in SH-SY5Y Cells

“…It is known that complex I is the main entry point of electrons into the respiratory chain and its inhibition results in the blockade of most of the oxidative metabolic reactions within mitochondria [ 52 ], providing support for the theory. Deficiency in complex I of the ETC has been described in PD [ 53 , 54 ] and AD patients [ 55 , 56 ], while decreased complex IV activity and ATP production [ 57 , 58 ] were reported in animal models of AD. In other words, in neurons, one of the 6-OHDA effects is complex I and IV inhibition, causing ATP levels to decrease, facilitating apoptosis.…”

“…In mitochondrial disorders, decreased ΔΨm and activity of the respiratory chain are observed with a simultaneous increase in ROS production [ 86 , 87 ]. Additionally, ΔΨm depolarization is generally correlated to neuronal death [ 54 , 88 ]. Mitochondrial depolarization induced by JNK was evaluated in Huh7 and HepG2 cells [ 89 ].…”

NIPSNAP protein family emerges as a sensor of mitochondrial health

“…[74] During metabolic stress, several pathological pathways are activated in mitochondria such as accumulation of ROS, opening of the mitochondria permeability transition pore, release of cytochrome c, and apoptosis. [96] Mitophagy supports neuronal survival by eliminating damaged mitochondria and inhibiting apoptosis. [96] Hence, defects in mitophagy result in accumulation of damaged mitochondria and ultimately lead to neurodegeneration.…”

“…[96] Mitophagy supports neuronal survival by eliminating damaged mitochondria and inhibiting apoptosis. [96] Hence, defects in mitophagy result in accumulation of damaged mitochondria and ultimately lead to neurodegeneration. [74] Cancer: One of the hallmarks of cancer cells is the ability to undergo metabolic reprograming, driven by the transcription factor HIF-1α, to generate ATP and cope with nutrient and metabolic stresses.…”

Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases

“…An in-depth understanding of the causes and mechanisms of each disease is essential for effective treatment of neurodegenerative diseases. These diseases are characterized by the selective loss of vulnerable populations of specific neurons due to various factors, such as increased number of reactive oxygen species [ 8 ], excitotoxicity [ 9 ], synaptic dysfunction [ 10 ], inflammation [ 11 ], impaired protein degradation systems [ 12 ], endoplasmic reticulum stress [ 13 ], and mitochondrial dysfunction [ 14 ]. Although the precise mechanism responsible for neuronal loss and functional disruption in these diseases still remains unknown, several studies have attempted treatment strategies through the protection of damaged neuronal cells.…”