The Regulation and Characterization of Mitochondrial-Derived Methylmalonic Acid in Mitochondrial Dysfunction and Oxidative Stress: From Basic Research to Clinical Practice

Liu, Yige; Wang, Shanjie; Zhang, Xiaoyuan; Cai, Hengxuan; Liu, Jinxin; Fang, Shaohong; Yu, Bo

doi:10.1155/2022/7043883

Cited by 10 publications

(7 citation statements)

References 103 publications

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“…A common characteristic of MMA, PA and cblC is an elevated oxidative stress. Previous studies demonstrated the presence of reactive oxygen species and oxidative damage in these diseases [47][48][49][50][51]. In addition, cblC lymphocytes were characterized by an imbalance between reduced/oxidized forms of glutathione [52].…”

Section: Discussionmentioning

confidence: 98%

Propionic Acidemia, Methylmalonic Acidemia, and cblC Defect: Comparison of Untargeted Metabolomic Profiles

Sidorina,

Catesini,

Sacchetti

et al. 2024

Preprint

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Methylmalonic acidemia (MMA), propionic acidemia (PA), and cobalamin C deficiency (cblC) share a defect in propionic acid metabolism. In addition, cblC is also involved in the process of homocysteine remethylation. These three diseases produce various phenotypes and complex downstream metabolic effects. In this study we used an untargeted metabolomics approach to investigate the biochemical differences and the possible connections with the pathophysiology of each disease. Untargeted urine metabolomic profiles of 21 patients (7 MMA, 7 PA, 7 cblC) were identified through statistical analysis (p&lt;0.05; log2FC &gt;|1|) and then used for the annotation. Annotated features were associated with different metabolic pathways potentially involved in the diseases development. Comparative statistic showed markedly different metabolomic profiles between MMA, PA and cblC, highlighting characteristic species for each disease. The most affected pathways were related to the metabolism of organic acids (MMA, PA, cblC), amino acids (MMA, PA, cblC), glycine and its conjugates (PA), transsulfuration pathway (cblC), oxidative processes (cblC) and neurosteroid hormones (cblC). The untargeted metabolomics study highlighted the presence of significant differences between the three diseases, pointing to the most relevant contrast of cblC profile compared to MMA and PA. Some new biomarkers are proposed for PA, while novel data regarding the alterations of steroid hormone profiles and biomarkers of oxidative stress were obtained for cblC disease. The elevation of neurosteroids in cblC may indicate a potential connection with the development of ocular and neuronal deterioration.

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Section: Discussionmentioning

confidence: 98%

Propionic Acidemia, Methylmalonic Acidemia, and cblC Defect: Comparison of Untargeted Metabolomic Profiles

Sidorina,

Catesini,

Sacchetti

et al. 2024

Preprint

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“…Epidemiological studies have shown that MMA is associated with the risk and poor prognosis of numerous chronic diseases, particularly diabetes, obesity, kidney dysfunction, and cardiovascular disease (9,22,23). In addition, there is growing evidence that high MMA levels may contribute to tumor progression and aggressiveness (17).…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…MMA is a marker of vitamin B12 deficiency and methylmalonic acidemia, a fatal and inherited heterogeneous disorder of MMA and vitamin B12 metabolism with a poor prognosis (6)(7)(8). Moreover, it has been widely reported as a potential biomarker involved in the progression and prognosis of chronic diseases such as cognitive impairment, cardiovascular events, and diabetes by inhibiting the tricarboxylic acid cycle (TCA cycle) and mitochondrial respiratory chain (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

On the Relationship between MMA Levels in Blood Products and Donor Sex, Age, and Donation Frequency

LI,

ZHU,

HUANG

et al. 2024

J Nutr Sci Vitaminol

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As the aging process accelerates, the age structure of blood donors turns to older and even aged groups. Methylmalonic acid (MMA), a byproduct of propionate metabolism, may be upregulated in the serum of older adults. As a mediator of chronic disease and tumor progression, the MMA content in blood products has become the focus of research. Absolute concentrations of MMA in blood products were determined based on the liquid chromatography-tandem mass spectrometry, so as to analyze how they were affected by donors' age, sex, and frequency of blood donation. The MMA content in leukocyte-depleted suspended red blood cell (lds-RBC) was significantly higher than that in fresh plasma (p,0.0001). The MMA content among five age groups showed no difference in either fresh plasma or lds-RBCs. The MMA content in fresh plasma was similar in the parameters of the sex, whereas that in lds-RBCs was higher in males than that in females (p50.035). There were no significant differences in MMA content when it comes to different frequencies of blood donors in either fresh plasma or lds-RBCs. Additionally, there was no significant difference or clear trend in the rate of elevated plasma MMA levels among different sexes, age groups, and blood donation frequency groups. MMA in the blood products from donors in China does not compromise the safety of blood transfusions for cancer patients. Nevertheless, there is a need to focus on MMA levels in Chinese and to develop race-specific and age-specific normal reference ranges.

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“…Although the specific mechanism is unclear, more attention should be paid to mitochondrial MMA metabolism itself for MMA increase in addition to cobalamin deficiency. Numerous studies demonstrated that MMA was a surrogate biomarker of mitochondrial dysfunction in humans and animals [ 13 – 16 , 30 – 32 ], which was more stable than mitochondrial oxidative products as a biomarker for mitochondria status [ 18 ]. Mitochondria have been considered the key regulatory centres located at the crossroads of complex cellular processes with myriad biochemical roles [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study

Wang

Guo

Liu

et al. 2023

Diabetol Metab Syndr

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Background Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes. Methods This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999–2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015. Results During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95%CIs) per doubling of MMA for all-cause mortality were 1.19 (1.04–1.37) in females with diagnosed diabetes versus 1.58 (1.36–1.86) in male counterparts. In addition, MMA levels had an insignificant or weak correlation with sex hormone profiles at baseline, regardless of diabetes status and sex. Conclusions Sex difference in mortality risk was especially significant in diagnosed type 2 diabetes. Increasing equivalent exposure to mitochondrial metabolite MMA was associated with a greater excess risk of future mortality in males with diabetes than in females.

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The Regulation and Characterization of Mitochondrial-Derived Methylmalonic Acid in Mitochondrial Dysfunction and Oxidative Stress: From Basic Research to Clinical Practice

Cited by 10 publications

References 103 publications

Propionic Acidemia, Methylmalonic Acidemia, and cblC Defect: Comparison of Untargeted Metabolomic Profiles

Propionic Acidemia, Methylmalonic Acidemia, and cblC Defect: Comparison of Untargeted Metabolomic Profiles

On the Relationship between MMA Levels in Blood Products and Donor Sex, Age, and Donation Frequency

Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study

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