Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity

Sharma, Rohit; Reimer, Bryn; Engelstad, Kristin; Skinner, Owen S.; Stackowitz, Erin; Haller, Ronald G.; Clish, Clary B.; Pierce, Kerry A.; Walker, Melissa; Fryer, Robert H.; Oglesbee, Devin; Mao, Xiangling; Shungu, Dikoma C.; Khatri, Ashok; Hirano, Michio; Vivo, Darryl C. De; Mootha, Vamsi K.

doi:10.1172/jci136055

Cited by 113 publications

(127 citation statements)

References 92 publications

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“…It is interesting that there is very little evidence about the function or role of the N-lactoyl-amino acids, but one study identified the process of their synthesis from lactate and amino acids by protease cytosolic nonspecific dipeptidase 2 by reverse proteolysis and hypothesized that this group of metabolites may represent a large portion of the unidentified metabolites that are regulated by exercise or other stimuli [ 36 ]. Recently, several N-lactoyl-amino acids have been linked to mitochondrial function [ 37 ], which is a crucial aspect of the thermogenic process efficiency.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

et al. 2021

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Cold exposure results in activation of metabolic processes required for fueling thermogenesis, potentially promoting improved metabolic health. However, the metabolic complexity underlying this process is not completely understood. We aimed to analyze changes in plasma metabolites related to acute cold exposure and their relationship to cold-acclimatization level and metabolic health in cold-acclimatized humans. Blood samples were obtained before and acutely after 10–15 min of ice-water swimming (<5 °C) from 14 ice-water swimmers. Using mass spectrometry, 973 plasma metabolites were measured. Ice-water swimming induced acute changes in 70 metabolites. Pathways related to amino acid metabolism were the most cold-affected and cold-induced changes in several amino acids correlated with cold-acclimatization level and/or metabolic health markers, including atherogenic lipid profile or insulin resistance. Metabolites correlating with cold-acclimatization level were enriched in the linoleic/α-linolenic acid metabolic pathway. N-lactoyl-tryptophan correlated with both cold-acclimatization level and cold-induced changes in thyroid and parathyroid hormones. Acute cold stress in cold-acclimatized humans induces changes in plasma metabolome that involve amino acids metabolism, while the linoleic and α-linolenic acid metabolism pathway seems to be affected by regular cold exposure. Metabolites related to metabolic health, thermogenic hormonal regulators and acclimatization level might represent prospective molecular factors important in metabolic adaptations to regular cold exposure.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

et al. 2021

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“…We recommend using blood instead of urine ketone measurements, both for ease of use and for improved accuracy in the setting of potential secondary mitochondrial deficits in ketone oxidation, where urinary acetoacetate may underestimate the degree of ketosis relative to blood beta-hydroxybutyrate. 83 …”

Section: Specific Care Aspectsmentioning

confidence: 99%

Friedreich Ataxia: Multidisciplinary Clinical Care

Lynch¹,

Schadt²,

Kichula³

et al. 2021

JMDH

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Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000–100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.

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“…The degree of heteroplasmy may explain this finding, as LHON lymphoblasts have a more severe mitochondrial defect (Complex-I), compared to POAG. A certain amount of defective Complex-I must be present before oxidative dysfunction occurs and clinical signs become apparent; this is known as the threshold effect [176]. The threshold for disease is lower in cells/tissues that are highly dependent on oxidative metabolism, such as RGCs versus tissues that are not, such as lymphocytes/lymphoblasts.…”

Section: Increased Nadhmentioning

confidence: 99%

Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

Petriti

Williams

Lascaratos

et al. 2021

Cells

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Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite best treatment, suggesting that other factors confer susceptibility. Several studies indicate that mitochondrial function may underlie both susceptibility and resistance to developing glaucoma. Mitochondria meet high energy demand, in the form of ATP, that is required for the maintenance of optimum retinal ganglion cell (RGC) function. Reduced nicotinamide adenine dinucleotide (NAD+) levels have been closely correlated to mitochondrial dysfunction and have been implicated in several neurodegenerative diseases including glaucoma. NAD+ is at the centre of various metabolic reactions culminating in ATP production—essential for RGC function. In this review we present various pathways that influence the NAD+(H) redox state, affecting mitochondrial function and making RGCs susceptible to degeneration. Such disruptions of the NAD+(H) redox state are generalised and not solely induced in RGCs because of high IOP. This places the NAD+(H) redox state as a potential systemic biomarker for glaucoma susceptibility and progression; a hypothesis which may be tested in clinical trials and then translated to clinical practice.

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Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity

Cited by 113 publications

References 92 publications

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

Friedreich Ataxia: Multidisciplinary Clinical Care

Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

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