In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder

Gallego, Lorena; Rivera-Barahona, Ana; Cuevas-Martín, Carmen; Guenzel, Adam J.; Pérez, Belén; Barry, Michael A.; Murphy, Michael P.; Logan, Angela; González-Quintana, Adrián; Martín, Miguel; Medina, Sonia; Gil‐Izquierdo, Ángel; Cuezva, José M.; Richard, Eva; Desviat, Lourdes R.

doi:10.1016/j.freeradbiomed.2016.04.007

Cited by 50 publications

(50 citation statements)

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“…As a starting point, we performed miRNA profiling in liver tissue of Pcca −/− (A138T) (PA) mice in which we had previously detected an altered bioenergetic and redox profile potentially contributing to the pathophysiology of the disease 25 . The analysis was performed by qRT-PCR with PA and wild-type (wt) mice samples (2 months-old, n = 4 per group) using PCR panels with pre-aliquoted primers for 752 miRNAs.…”

Section: Resultsmentioning

confidence: 99%

“…We performed in silico analysis of predicted and validated targets of the dysregulated miRNAs using different bioinformatic tools and databases (miRBase TargetScan, MiRTarBase), as well as a review of published studies including analyzed targets and pathways involved in disease processes for each miRNA. We and other authors have reported that mitochondrial dysfunction and oxidative stress are probable key players in the pathophysiology of PA 24, 25 , which led us to select three miRNAs for further studies, miR-34a-5p, miR-338-3p and miR-350, due to their involvement in these processes. miR-34a-5p targets Bcl2 , Sirt1 and Notch1 genes, influencing apoptosis and mitochondrial energy metabolism, among other processes 29, 30 ; miR-338-3p regulates the expression of several subunits of mitochondrial oxidative phosphorylation complexes 31 , and miR-350 regulates p38 and JNK stress kinases 32 .…”

Section: Resultsmentioning

confidence: 99%

“…PCC catalyzes the carboxylation of propionyl-CoA, derived from the catabolism of several amino acids, cholesterol side chain and odd-chain fatty acids, to D-methylmalonyl-CoA, which eventually enters the Krebs cycle 23 . In vivo and in vitro evidence points to the pathogenic role of a secondary mitochondrial dysfunction induced by accumulated toxic metabolites resulting in cellular oxidative damage 24, 25 .…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia

Rivera-Barahona

Fulgencio-Covián

Pérez‐Cerdá

et al. 2017

Sci Rep

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miRNome expression profiling was performed in a mouse model of propionic acidemia (PA) and in patients’ plasma samples to investigate the role of miRNAs in the pathophysiology of the disease and to identify novel biomarkers and therapeutic targets. PA is a potentially lethal neurometabolic disease with patients developing neurological deficits and cardiomyopathy in the long-term, among other complications. In the PA mouse liver we identified 14 significantly dysregulated miRNAs. Three selected miRNAs, miR-34a-5p, miR-338-3p and miR-350, were found upregulated in brain and heart tissues. Predicted targets involved in apoptosis, stress-signaling and mitochondrial function, were inversely found down-regulated. Functional analysis with miRNA mimics in cellular models confirmed these findings. miRNA profiling in plasma samples from neonatal PA patients and age-matched control individuals identified a set of differentially expressed miRNAs, several were coincident with those identified in the PA mouse, among them miR-34a-5p and miR-338-3p. These two miRNAs were also found dysregulated in childhood and adult PA patients’ cohorts. Taken together, the results reveal miRNA signatures in PA useful to identify potential biomarkers, to refine the understanding of the molecular mechanisms of this rare disease and, eventually, to improve the management of patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia

Rivera-Barahona

Fulgencio-Covián

Pérez‐Cerdá

et al. 2017

Sci Rep

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“…Propionic acid, propionylcarnitine and MC can prevent normal function of the potassium channels of the heart (like KCNH2) resulting in delay re-polarization which can manifest as prolonged QTc [70]. This dysfunction has been postulated to explain the cardiac arrhythmias observed in PA. Elevated propionyl-CoA intermediates and oxidative stress molecules which impact TCA and oxidative phosphorylation function are also implicated in the cardiomyopathy seen [71, 72]. Other studies have shown that there appears to be tissue specific deficiencies in CoQ10 and carnitine [73, 74].…”

Section: Reviewmentioning

confidence: 99%

“…Inflammation and reactive oxygen species (ROS) appear to be elevated in individuals with PA and their tissues [71, 79–81]. ROS levels assayed in fibroblasts from individuals with PA after antioxidant use, showed some improvement.…”

Section: Reviewmentioning

confidence: 99%

Propionyl-CoA carboxylase – A review

Wongkittichote

Mew

Chapman

2017

Molecular Genetics and Metabolism

175

159

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Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer. Dysfunction of PCC leads to the inherited metabolic disorder propionic acidemia, which can result in an affected individual presenting with metabolic acidosis, hyperammonemia, lethargy, vomiting and sometimes coma and death if not treated. Individuals with propionic acidemia also have a number of long term complications resulting from the dysfunction of the PCC enzyme. Here we present an overview of the current knowledge about the structure and function of PCC. We review an updated list of human variants which are published and provide an overview of the disease.

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Evidence That Long‐Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway

dos Reis,

Becker,

Marchetti

et al. 2024

American J of Med Genetics Pt A

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Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders clinically characterized by metabolic decompensation associated with life‐threatening encephalopathic episodes in the neonatal period. Adequate and rapid therapeutic management is essential for patients' survival and prognosis. In this study, a restricted protein diet associated with L‐carnitine (LC) supplementation was shown to decrease mortality and morbidity in patients affected by these disorders probably by decreasing the accumulation of the major metabolites and therefore their toxicity. Since oxidative stress was proposed as a contributing mechanism of tissue damage in PAcidemia and MMAcidemia and LC has potent antioxidant properties, our objective in this work was to investigate the effects of a long‐term therapy consisting of reduced protein intake associated with LC supplementation on oxidative damage markers in patients affected by these diseases. We measured urinary isoprostanes, di‐tyrosine, and oxidized guanine species, which reflect oxidative damage to lipids, proteins, and DNA/RNA, respectively, as well as the concentrations of NO products (nitrate plus nitrite) in patients untreated or submitted to short‐term or a long‐term treatment. Results revealed significant increases of isoprostanes, di‐tyrosine, and oxidized guanine species, as well as a moderate nonsignificant increase of NO levels in the untreated patients, relatively to controls. Furthermore, these altered markers were attenuated after short‐term treatment and normalized after prolonged treatment. In conclusion, data from this work show for the first time that long‐standing treatment of patients with disorders of the propionate pathway can protect against oxidative damage. However, it remains to be elucidated whether oxidative stress identified in this study directly correlates with the clinical conditions of the affected patients.

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In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder

Cited by 50 publications

References 53 publications

Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia

Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia

Propionyl-CoA carboxylase – A review

Evidence That Long‐Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway

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