The mitochondria‐targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model

Abstract

Primary mitochondrial diseases (PMD) are inherited diseases that cause dysfunctional mitochondrial oxidative phosphorylation, leading to diverse multisystem diseases and substantially impaired quality of life. PMD treatment currently comprises symptom management, with an unmet need for therapies targeting the causative mitochondrial defects. Molecules which selective target mitochondria have been proposed as potential treatment options in PMD but have met with limited success. We have previously shown in animal models that mitochondrial dysfunction caused by the disease process could be prevented and/or reversed by selective targeting of the “gasotransmitter” hydrogen sulfide (H2S) to mitochondria using a novel compound, AP39. Therefore, in this study we investigated whether AP39 could also restore mitochondrial function in PMD models where mitochondrial dysfunction was the cause of the disease pathology using C. elegans. We characterised several PMD mutant C. elegans strains for reduced survival, movement and impaired cellular bioenergetics and treated each with AP39. In animals with widespread electron transport chain deficiency (gfm‐1[ok3372]), AP39 (100 nM) restored ATP levels, but had no effect on survival or movement. However, in a complex I mutant (nuo‐4[ok2533]), a Leigh syndrome orthologue, AP39 significantly reversed the decline in ATP levels, preserved mitochondrial membrane potential and increased movement and survival. For the first time, this study provides proof‐of‐principle evidence suggesting that selective targeting of mitochondria with H2S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders.

Progress and perspective on hydrogen sulfide donors and their biomedical applications

“…In addition, the naproxen‐ 306,328 (compound 78 , Figure 9), sulindac‐ 306 (compound 79 , Figure 9), and ibuprofen‐ 306 (compound 80 , Figure 9) derived hybrid compounds were also reported to have anticancer activities, 297 apart from their potent anti‐inflammatory activity without obvious gastrointestinal toxicity. AP39 (compound 81 , Figure 9), a mitochondria‐targeted H 2 S‐releasing compound, was reported to elevate the H 2 S concentration in mitochondria of microvascular endothelial cells, thereby leading to the stimulation of cellular bioenergetics, preservation of mitochondrial DNA integrity, and eventual prevention of cells from oxidative stress‐mediated damages 329,330 . In recent years, AP39 was disclosed to have significant therapeutical/preventive effects on pre‐eclampsia, 331 to exert prevention against myocardial reperfusion injury 332 and brain ischemia, 333 to protect dermal fibroblasts from UVA‐induced photoaging 334 and organ grafts from ischemia–reperfusion injury, 335,336 and so on.…”

“…AP39 (compound 81, Figure 9), a mitochondria-targeted H 2 S-releasing compound, was reported to elevate the H 2 S concentration in mitochondria of microvascular endothelial cells, thereby leading to the stimulation of cellular bioenergetics, preservation of mitochondrial DNA integrity, and eventual prevention of cells from oxidative stress-mediated damages. 329,330 In recent years, AP39 was disclosed to have significant therapeutical/preventive effects on pre-eclampsia, 331 to exert prevention against myocardial reperfusion injury 332 and brain ischemia, 333 to protect dermal fibroblasts from UVA-induced photoaging 334 and organ grafts from ischemia-reperfusion injury, 335,336 and so on. Most recently, researchers have identified pharmacological effects of AP39 in the onset and progression of Duchenne muscular dystrophy pathology.…”

Leigh Syndrome: A Tale of Two Genomes

“…These mutant strains have allowed for modeling respiratory chain dysfunction and investigating in vivo mitochondrial functions associated with these defects ( Kayser et al, 2004 ; Lemire et al, 2009 ; Dingley et al, 2010 ). These types of studies where mutations are introduced to study disease phenotypes while screening for targeted therapeutics continue to provide valuable information on mechanisms underlying the mutation variants involved in LS and other respiratory chain disorders ( Diaz, 2010 ; Polyak et al, 2018 ; Maglioni et al, 2020 ; Fox et al, 2021 ).…”

The Role of Protein Persulfidation in Brain Aging and Neurodegeneration

“…Particularly interesting could be mitochondria-targeted H 2 S donors (Le Trionnaire et al, 2014 ). For example, AP39 is known to generally improve mitochondrial bioenergetics (Gero et al, 2016 ; Etheridge et al, 2017 ; Fox et al, 2021 ) and supplementation of APP/PS1 mouse model of AD P39 improved mitochondrial dynamics, shifting from fission toward fusion, ameliorated their spatial memory deficits and reduced Aβ deposition in their brains (Zhao et al, 2016 ).…”