Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem
Tomonori Hara1,2, Manabu Toyoshima1, Yasuko Hisano1
1Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
Abstract:
Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.
Insights
Disrupting the GLO1 gene increases vulnerability to carbonyl stress, impacting human stem cell-derived neurons and mitochondria. This suggests a mechanism for schizophrenia and potential therapeutic targets for carbonyl stress-related diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Carbonyl stress, a type of oxidative stress, is implicated in schizophrenia's pathophysiology.
- The precise mechanisms linking carbonyl stress to neurological disorders remain largely unexplored.
Purpose of the Study:
- To investigate the role of Glyoxalase 1 (GLO1) in cellular defense against carbonyl stress.
- To elucidate the impact of GLO1 disruption on human induced pluripotent stem cells (hiPSCs) and their neuronal derivatives.
Main Methods:
- Generated GLO1 knockout (KO) hiPSCs to model carbonyl stress vulnerability.
- Administered methylglyoxal (MGO), a reactive carbonyl compound, to GLO1 KO-hiPSCs and derived neurons.
- Assessed cellular viability, caspase-3 activity, neurite extension, cell migration, protein modification, and mitochondrial function.
Main Results:
- GLO1 KO-hiPSCs exhibited reduced viability and increased caspase-3 activity upon MGO exposure.
- MGO impaired neurite extension and migration in GLO1 KO-hiPSC-derived neurons.
- Accumulation of methylglyoxal-derived hydroimidazolone (MG-H1)-modified proteins and mitochondrial dysfunction were observed in GLO1 KO cells.
Conclusions:
- GLO1 deficiency exacerbates cellular damage from carbonyl stress, particularly affecting mitochondrial function.
- These findings highlight a potential mechanism for carbonyl stress in neurological diseases like schizophrenia.
- Pyridoxamine, a carbonyl scavenger, showed partial rescue effects, suggesting therapeutic potential.
