Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function

Abstract

Neurotoxicity is induced by different toxic substances, including environmental chemicals, drugs, and pathogenic toxins, resulting in oxidative damage and neurodegeneration in mammals. The nervous system is extremely vulnerable to oxidative stress because of its high oxygen demand. Mitochondria are the main source of ATP production in the brain neuron, and oxidative stress-caused mitochondrial dysfunction is implicated in neurodegenerative diseases. H2S was initially identified as a toxic gas; however, more recently, it has been recognized as a neuromodulator as well as a neuroprotectant. Specifically, it modulates mitochondrial activity, and H2S oxidation in mitochondria produces various reactive sulfur species, thus modifying proteins through sulfhydration. This review focused on highlighting the neuron modulation role of H2S in regulating neurodegenerative diseases through anti-oxidative, anti-inflammatory, anti-apoptotic and S-sulfhydration, and emphasized the importance of H2S as a therapeutic molecule for neurological diseases.

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis—A Comprehensive One-Year Review

“…Physiological concentrations of H 2 S are generally associated with cytoprotection against oxidative stress [ 83 ]. However, elevated H 2 S levels can contribute to oxidative stress, especially under pathophysiological conditions [ 10 ]. This paradoxical effect is primarily due to the ability of high concentrations of H 2 S to inhibit cytochrome c oxidase, a specific enzyme in the mitochondrial electron transport chain.…”

“…Cell homeostasis refers to maintaining a stable, constant cell condition governed by a complex network of regulatory mechanisms [ 92 , 93 ]. H 2 S, acting as a gasotransmitter, has been increasingly involved in numerous physiological processes integral to maintaining cellular homeostasis [ 10 , 94 ].…”

“…H 2 S’s multifaceted role in modulating lipid peroxidation and cellular redox balance positions it as a potent inhibitor of ferroptosis. Its capacity to scavenge lipid peroxides and ROS and promote the expression of antioxidant enzymes, such as glutathione peroxidase 4 (GPX4), highlights its regulatory prowess in thwarting ferroptotic processes [ 10 , 41 ].…”

“…This shift in perception is due to the recognition of H 2 S as a significant player in diverse physiological and pathological processes [ 4 ]. This small molecule, considered as the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO), exerts a plethora of effects in mammalian physiology, such as vasodilation [ 5 ], vascular tone [ 6 ], modulating the inflammatory response [ 7 , 8 ], neurotransmission [ 9 ], antioxidant properties [ 10 ], apoptosis [ 11 ] cellular survival [ 12 ], regulating cellular metabolism [ 13 ], or acting as a cytoprotectant [ 14 ]. As a multifaceted molecule [ 15 , 16 ] with profound biological implications, H 2 S has increasingly been at the center of scientific scrutiny.…”

“…It also exerts anti-inflammatory effects by inhibiting NF-κB activation. Additionally, H 2 S displays cytoprotective effects by scavenging ROS and enhancing antioxidant enzyme activities, mitigating oxidative stress and cellular damage [ 10 , 41 ].…”