Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice
Catarina M Quinzii1, Caterina Garone, Valentina Emmanuele
1Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
Abstract:
Primary human CoQ(10) deficiencies are clinically heterogeneous diseases caused by mutations in PDSS2 and other genes required for CoQ(10) biosynthesis. Our in vitro studies of PDSS2 mutant fibroblasts, with <20% CoQ(10) of control cells, revealed reduced activity of CoQ(10)-dependent complex II+III and ATP synthesis, without amplification of reactive oxygen species (ROS), markers of oxidative damage, or antioxidant defenses. In contrast, COQ2 and ADCK3 mutant fibroblasts, with 30-50% CoQ(10) of controls, showed milder bioenergetic defects but significantly increased ROS and oxidation of lipids and proteins. We hypothesized that absence of oxidative stress markers and cell death in PDSS2 mutant fibroblasts were due to the extreme severity of CoQ(10) deficiency. Here, we have investigated in vivo effects of Pdss2 deficiency in affected and unaffected organs of CBA/Pdss2(kd/kd) mice at presymptomatic, phenotypic-onset, and end-stages of the disease. Although Pdss2 mutant mice manifest widespread CoQ(9) deficiency and mitochondrial respiratory chain abnormalities, only affected organs show increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced citrate synthase activity, an index of mitochondrial mass. Our data indicate that kidney-specific loss of mitochondria triggered by oxidative stress may be the cause of renal failure in Pdss2(kd/kd) mice.
Insights
Primary Coenzyme Q10 (CoQ10) deficiencies cause varied diseases. Severe PDSS2 mutations in mice lead to organ-specific mitochondrial loss and renal failure due to oxidative stress.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Primary Coenzyme Q10 (CoQ10) deficiencies are heterogeneous genetic disorders impacting CoQ10 biosynthesis.
- Mutations in PDSS2, COQ2, and ADCK3 genes lead to distinct cellular phenotypes in CoQ10 deficiency.
Purpose of the Study:
- To investigate the in vivo effects of Pdss2 deficiency in mice.
- To determine the role of oxidative stress in organ-specific pathology of CoQ10 deficiency.
Main Methods:
- Utilized a mouse model (CBA/Pdss2(kd/kd)) to study Pdss2 deficiency across disease stages.
- Analyzed CoQ9 levels, mitochondrial respiratory chain activity, reactive oxygen species (ROS) production, oxidative damage markers, and mitochondrial mass (citrate synthase activity) in affected and unaffected organs.
Main Results:
- Pdss2 mutant mice exhibited widespread CoQ9 deficiency and mitochondrial dysfunction.
- Affected organs showed increased ROS production, oxidative stress, mitochondrial DNA depletion, and reduced mitochondrial mass.
- Kidney-specific mitochondrial loss, driven by oxidative stress, was observed in Pdss2(kd/kd) mice.
Conclusions:
- Severe CoQ10 deficiency due to PDSS2 mutations causes organ-specific mitochondrial dysfunction and failure.
- Oxidative stress plays a critical role in the pathogenesis of renal failure in Pdss2(kd/kd) mice.
- These findings highlight the complex interplay between CoQ10 levels, oxidative stress, and organ integrity in primary CoQ10 deficiencies.
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