Pathophysiological mechanisms of complications associated with propionic acidemia

Marchuk, Hannah; Wang, You; Ladd, Zachary Alec; Chen, Xiaoxin; Zhang, Guo-Fang

doi:10.1016/j.pharmthera.2023.108501

Cited by 5 publications

(8 citation statements)

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“…[64] Mutation in mtDNA or DNA encoding mitochondrial proteins can lead to severe hereditary diseases like mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), [65] Leber's hereditary optic neuropathy (LHON) [66] and propionic acidemia (PA) (Figure 3A). [67] Additionally, owing to limited intron presence and self-repair mechanisms, mtDNA is more susceptible to mutations and damage compared to nDNA. Mutations in mtDNA have been implicated in the aging process, carcinogenic mechanisms, and several common diseases such as neuronal degeneration and cardiovascular disease.…”

Section: Loss Of Mitochondrial Quality Controlmentioning

confidence: 99%

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

Long,

Liu,

Nan

et al. 2024

Advanced Materials

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Mitochondria, widely known as the energy factories of eukaryotic cells, have a myriad of vital functions across diverse cellular processes. Dysfunctions within mitochondria serve as catalysts for various diseases, prompting widespread cellular demise. Mounting research on remedying damaged mitochondria indicates that mitochondria constitute a valuable target for therapeutic intervention against diseases. But the less clinical practice and lower recovery rate imply the limitation of traditional drugs, which need a further breakthrough. Nanotechnology has approached favorable regiospecific biodistribution and high efficacy by capitalizing on excellent nanomaterials and targeting drug delivery. Mitochondria‐remedying nanodrugs have achieved ideal therapeutic effects. In this review, we have elucidated the significance of mitochondria in various cells and organs, while also compiling mortality data for related diseases. Correspondingly, nanodrug‐mediate therapeutic strategies and applicable mitochondria‐remedying nanodrugs in disease were detailed, with a full understanding of the roles of mitochondria dysfunction and the advantages of nanodrugs. In addition, the future challenges and directions have been widely discussed. In conclusion, this review provides comprehensive insights into the design and development of mitochondria‐remedying nanodrugs, aiming to help scientists who desire to extend their research fields and engage in this interdisciplinary subject.This article is protected by copyright. All rights reserved

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Section: Loss Of Mitochondrial Quality Controlmentioning

confidence: 99%

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

Long,

Liu,

Nan

et al. 2024

Advanced Materials

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“…Propionate, odd-chain fatty acids, side-chain of cholesterol, and propiogenic amino acids such as valine, isoleucine, methionine, and threonine are all metabolic precursors of propionyl-CoA 5 , 11 . Any modulation of the metabolism of these compounds linked to propionyl-CoA will impact PA.…”

Section: Introductionmentioning

confidence: 99%

“…Decreased PCC activity disrupts the conversion of propionyl-CoA into methylmalonyl-CoA and its subsequent entry into the tricarboxylic acid (TCA) cycle, an anaplerotic process within mitochondria. The advancement of PA can give rise to a range of complications, and inadequate management of this condition poses life-threatening risks [1][2][3][4][5][6][7][8][9][10][11] .While the precise pathological mechanisms underlying various complications associated with PA remain incompletely understood, it is clear that the accumulation of propionyl-CoA and its toxic metabolites plays a significant role as pathogenic factors. This is primarily due to the structural similarity between acetyl-CoA (C2 CoA) and propionyl-CoA (C3 CoA), where the increased levels of C3 CoA can result in metabolic crises through competition with C2 CoA.…”

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confidence: 99%

“…For example, when C3 CoA displaces C2 CoA, it contributes to the formation of propionylglutamate 12 , methylcitrate [13][14][15][16] , and odd-chain fatty acids [17][18][19][20] , which disrupt normal urea metabolism 21,22 , the TCA cycle 14,23 , and lipid metabolism 24 . Consequently, the ratio of C3 CoA to C2 CoA becomes a reliable indicator for assessing the severity of metabolic disturbances in PA patients [25][26][27] .Propionate, odd-chain fatty acids, side-chain of cholesterol, and propiogenic amino acids such as valine, isoleucine, methionine, and threonine are all metabolic precursors of propionyl-CoA 5,11 . Any modulation of the metabolism of these compounds linked to propionyl-CoA will impact PA.…”

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confidence: 99%

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confidence: 99%

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Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation

He,

Marchuk,

Koeberl

et al. 2024

Commun Biol

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Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.

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Aminotransferase trends in propionic acidemia

Silva,

Raski,

Charrow

et al. 2024

American J of Med Genetics Pt A

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Propionic acidemia is a metabolic condition with multiple serious acute and chronic presentations that require strict monitoring. Literature on liver function abnormalities in propionic acidemia is scarce, and the mechanism of liver impairment in this condition remains unclear. Currently, there is no indication for liver‐function tests during follow‐up and their clinical or prognostic utility is unknown. This study aimed to determine aminotransferase trends in individuals with propionic acidemia at a single institution. We retrospectively evaluated and classified the aminotransferases of 12 patients with propionic acidemia during hospital admissions and routine office visits. The present findings suggest that aminotransferase elevations are very common in this population and can persist beyond acute illness. During hospitalization events, aminotransferases were not a predictor of severity, duration of stay, and readmission within 1 month. Understanding aminotransferase trends in these patients will help clinicians make decisions in the acute setting and potentially in the follow‐up of new therapies.

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Pathophysiological mechanisms of complications associated with propionic acidemia

Cited by 5 publications

References 243 publications

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation

Aminotransferase trends in propionic acidemia

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