| Citation |
Polyak E, Ostrovsky J, Peng M, Dingley SD, Tsukikawa M, Kwon YJ, McCormack SE, Bennett M, Xiao R, Seiler C, Zhang Z, Falk MJ. N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.
Mol Genet Metab, 2018. |
Full Description
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Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
Experimental Details:
WBPaper00053833:01_N2_untreated_adult_rep1
WBPaper00053833:02_N2_untreated_adult_rep2
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WBPaper00053833:04_N2_untreated_adult_rep4
WBPaper00053833:05_N2_untreated_adult_rep5
WBPaper00053833:06_N2_untreated_adult_rep6
WBPaper00053833:07_gas-1(fc21)_untreated_adult_rep7
WBPaper00053833:08_gas-1(fc21)_VitaminC_adult_rep8
WBPaper00053833:09_gas-1(fc21)_OroticAcid_adult_rep9
WBPaper00053833:10_gas-1(fc21)_LipoicAcid_adult_rep10
WBPaper00053833:11_gas-1(fc21)_N-Acetylcysteine_adult_rep11
WBPaper00053833:12_gas-1(fc21)_MS010_adult_rep12
WBPaper00053833:13_gas-1(fc21)_CoenzymeQ10_adult_rep13
WBPaper00053833:14_gas-1(fc21)_Decyl-TPP_adult_rep14
WBPaper00053833:15_gas-1(fc21)_untreated_adult_rep15
WBPaper00053833:16_gas-1(fc21)_VitaminC_adult_rep16
WBPaper00053833:17_gas-1(fc21)_OroticAcid_adult_rep17
WBPaper00053833:18_gas-1(fc21)_LipoicAcid_adult_rep18
WBPaper00053833:19_gas-1(fc21)_N-Acetylcysteine_adult_rep19
WBPaper00053833:20_gas-1(fc21)_MS010_adult_rep20
WBPaper00053833:21_gas-1(fc21)_CoenzymeQ10_adult_rep21
WBPaper00053833:22_gas-1(fc21)_Decyl-TPP_adult_rep22
WBPaper00053833:23_gas-1(fc21)_untreated_adult_rep23
WBPaper00053833:24_gas-1(fc21)_VitaminC_adult_rep24
WBPaper00053833:25_gas-1(fc21)_OroticAcid_adult_rep25
WBPaper00053833:26_gas-1(fc21)_LipoicAcid_adult_rep26
WBPaper00053833:27_gas-1(fc21)_N-Acetylcysteine_adult_rep27
WBPaper00053833:28_gas-1(fc21)_MS010_adult_rep28
WBPaper00053833:29_gas-1(fc21)_CoenzymeQ10_adult_rep29
WBPaper00053833:30_gas-1(fc21)_Decyl-TPP_adult_rep30
WBPaper00053833:31_gas-1(fc21)_untreated_adult_rep31
WBPaper00053833:32_gas-1(fc21)_VitaminC_adult_rep32
WBPaper00053833:33_gas-1(fc21)_OroticAcid_adult_rep33
WBPaper00053833:34_gas-1(fc21)_LipoicAcid_adult_rep34
WBPaper00053833:35_gas-1(fc21)_N-Acetylcysteine_adult_rep35
WBPaper00053833:36_gas-1(fc21)_MS010_adult_rep36
WBPaper00053833:37_gas-1(fc21)_CoenzymeQ10_adult_rep37
WBPaper00053833:38_gas-1(fc21)_Decyl-TPP_adult_rep38
WBPaper00053833:39_N2_untreated_L1_rep39
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WBPaper00053833:42_N2_untreated_L1_rep42
WBPaper00053833:43_N2_untreated_L1_rep43
WBPaper00053833:44_gas-1(fc21)_untreated_L1_rep44
WBPaper00053833:45_gas-1(fc21)_VitaminC_L1_rep45
WBPaper00053833:46_gas-1(fc21)_OroticAcid_L1_rep46
WBPaper00053833:47_gas-1(fc21)_LipoicAcid_L1_rep47
WBPaper00053833:48_gas-1(fc21)_N-Acetylcysteine_L1_rep48
WBPaper00053833:49_gas-1(fc21)_MS010_L1_rep49
WBPaper00053833:50_gas-1(fc21)_CoenzymeQ10_L1_rep50
WBPaper00053833:51_gas-1(fc21)_Decyl-TPP_L1_rep51
WBPaper00053833:52_gas-1(fc21)_untreated_L1_rep52
WBPaper00053833:53_gas-1(fc21)_VitaminC_L1_rep53
WBPaper00053833:54_gas-1(fc21)_OroticAcid_L1_rep54
WBPaper00053833:55_gas-1(fc21)_LipoicAcid_L1_rep55
WBPaper00053833:56_gas-1(fc21)_N-Acetylcysteine_L1_rep56
WBPaper00053833:57_gas-1(fc21)_MS010_L1_rep57
WBPaper00053833:58_gas-1(fc21)_CoenzymeQ10_L1_rep58
WBPaper00053833:59_gas-1(fc21)_Decyl-TPP_L1_rep59
WBPaper00053833:60_gas-1(fc21)_untreated_L1_rep60
WBPaper00053833:61_gas-1(fc21)_VitaminC_L1_rep61
WBPaper00053833:62_gas-1(fc21)_OroticAcid_L1_rep62
WBPaper00053833:63_gas-1(fc21)_LipoicAcid_L1_rep63
WBPaper00053833:64_gas-1(fc21)_N-Acetylcysteine_L1_rep64
WBPaper00053833:65_gas-1(fc21)_MS010_L1_rep65
WBPaper00053833:66_gas-1(fc21)_CoenzymeQ10_L1_rep66
WBPaper00053833:67_gas-1(fc21)_Decyl-TPP_L1_rep67
WBPaper00053833:68_gas-1(fc21)_untreated_L1_rep68
WBPaper00053833:69_gas-1(fc21)_VitaminC_L1_rep69
WBPaper00053833:70_gas-1(fc21)_OroticAcid_L1_rep70
WBPaper00053833:71_gas-1(fc21)_LipoicAcid_L1_rep71
WBPaper00053833:72_gas-1(fc21)_N-Acetylcysteine_L1_rep72
WBPaper00053833:73_gas-1(fc21)_MS010_L1_rep73
WBPaper00053833:74_gas-1(fc21)_CoenzymeQ10_L1_rep74
WBPaper00053833:75_gas-1(fc21)_Decyl-TPP_L1_rep75. |
