Biology subjects

Baumgartner, M. R.

Publications and source records attributed to Baumgartner, M. R..

8 recordsLinked to original sources

bioRxiv2026

Disturbed mitochondrial energy production in methylmalonic aciduria is cell-type and variant-dependent

Methylmalonic aciduria (MMA) is caused by deficiency of methylmalonyl-CoA mutase (MMUT), which catalyses the final step of propionate catabolism and fuels the tricarboxylic acid cycle for energy production. Previous studies reported disrupted mitochondrial homeostasis in MMA, including reduced mitochondrial membrane potential and increased oxidative stress, especially in energetically demanding and chronically affected tissues like brain and kidneys. However, how these changes impact mitochondrial energy production remains unclear. Here, we systematically investigated mitochondrial energy production using extracellular flux analysis in cellular models of MMA, including 293T cells, patient-derived fibroblasts, urine-derived epithelial kidney cells and induced pluripotent stem cells (iPSCs) as well as iPSC-derived neurons harbouring either complete loss (knockout, KO) or pathogenic missense variants in MMUT. We found no impact on mitochondrial energy production in MMUT-KO 293T cells and fibroblasts compared to controls. In contrast, fibroblasts and 293T cells expressing the pathogenic MMUT-p.N219Y variant showed decreased energy production. This corresponds to the altered mitochondrial membrane potential in 293T cells, but contrasts with their unchanged mitochondrial abundance. Depletion of glucose, glutamine and pyruvate from the media or provision of each individually as sole fuel source exacerbated the phenotype of MMUT-p.N219Y clones, but did not induce a phenotype in MMUT-KO 293T cells. Finally, we confirmed reduced mitochondrial energy production in patient-derived kidney cells but found no evidence in MMUT-p.N219Y iPSCs and their derived neurons. Overall, our work suggests that the impact of MMUT-deficiency on mitochondrial energy production is cell type- and variant-dependent. Further investigations should clarify molecular mechanisms and their clinical impact.

cell biology↗

bioRxiv2025

Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are two types of substituted amphetamines that share structural-chemical similarities but exhibit contrasting acute and chronic effects including addictive liability. Tryptophan (TRY) pathways are involved in pleiotropic physiological functions at the interface of brain-body connections. Preclinical evidence suggests that amphetamines may modulate these pathways and, thus, indirectly influence brain functions via persistent alterations of peripheral metabolites. However, little is known about alterations of TRY-related metabolites in the blood and their clinical implications in chronic users of MDMA and METH. Hence, we characterized serum levels of TRY-related metabolites in a comparative cross-sectional study including n=36 chronic MDMA users, n=33 chronic METH users, and n=71 sex-matched, stimulant-naive healthy controls (Ntotal=140). An ultra- high performance liquid chromatography-mass spectrometry method was used to determine TRY metabolites. Combining metabolite levels, metabolic ratios, and network analysis we found robust evidence of divergent pathway alterations between METH and MDMA users. Chronic METH use was particularly associated with a depletion of serum TRY and serotonin levels, and a general activation of kynurenine pathways, while chronic MDMA use was linked to a selective activation of the OH-kynurenine metabolic branch. Metabolite changes were associated with the severity of psychopathology in the depression and psychosis domains across groups. Altogether, our findings demonstrate differential changes of serum TRY pathways in chronic MDMA and METH users. Persistent alterations of these pathways might contribute to the contrasting clinical profile of the substances and constitute a peripheral dimension of neurochemical plasticity with relevant implications for therapeutic targets.

biochemistry↗

bioRxiv2024

Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria

Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of 2-dimethyloxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.

neuroscience↗

bioRxiv2023

Plasma endocannabinoids in cocaine dependence and their interaction with cocaine craving and metabotropic glutamate receptor 5 density in the human brain

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N=103; 69 recreational CU and 34 dependent CU) and stimulant-naive healthy controls (N=92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N=33; controls: N=43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N=18; controls: N=16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

neuroscience↗

bioRxiv2021

Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria

Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria (MMAuria), present unique challenges to energetic homeostasis by disrupting energy producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut) type MMAuria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared to littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these indicate hypometabolism, energetic inflexibility and increased stores at the expense of active tissue as energy shortage consequences.

physiology↗

bioRxiv2020

Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase

Cobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds - cobamides - that are found in food and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology.

biochemistry↗

bioRxiv2018

Genetic, structural, and functional analysis of mutations causing methylmalonyl-CoA epimerase deficiency

Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of D-methylmalonyl-CoA and L-methylmalonyl-CoA in propionate catabolism. Autosomal recessive mutations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with mutations in MCEE. Nine patients were homozygous for the known nonsense mutation p.Arg47* (c.139C>T), and one for the novel missense mutation p.Ile53Arg (c.158T>G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described patient mutations p.Lys60Gln and p.Arg143Cys, onto our 1.8 [A] structure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this mutation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. We solved the structure of MCEE-Arg143Cys to 1.9 [A] and found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria.

biochemistry↗

bioRxiv2018

Self-regulation of the Dopaminergic Reward Circuit in Cocaine Users with Mental Imagery and Neurofeedback

Background: Enhanced drug-related reward sensitivity accompanied by impaired sensitivity to non-drug related rewards in the mesolimbic dopamine system are thought to underlie the broad motivational deficits and dysfunctional decision-making frequently observed in cocaine use disorder (CUD). Effective approaches to modify this imbalance and reinstate non-drug reward responsiveness are urgently needed. Here we examine whether cocaine users (CU) can use mental imagery of non-drug rewards to self-regulate the ventral tegmental area and substantia nigra (VTA/SN). We expected that compulsive and obsessive thoughts about cocaine consumption would hamper the ability to self-regulate the VTA/SN. Finally, we tested if self-regulation of the VTA/SN can be improved with real-time fMRI (rtfMRI) neurofeedback (NFB).\n\nMethods: Twenty-two CU and 28 healthy controls (HC) were asked to voluntarily up-regulate VTA/SN activity with rewarding non-drug imagery alone, or combined with rtfMRI NFB of VTA/SN activity. Obsessive-compulsive drug use was measured with the Obsessive Compulsive Cocaine Use Scale (OCCUS).\n\nResults: CU were able to induce activity in the dopaminergic midbrain and other reward regions with reward imagery. The ability to self-regulate the VTA/SN was reduced in those with more severe obsessive-compulsive drug use. NFB enhanced the effect of non-drug imagery.\n\nConclusion: CU can voluntary activate their reward system through non-drug related imagery and improve this ability with rtfMRI NFB. Combining reward imagery and rtFMRI NFB has great potential for modifying the maladapted reward sensitivity and reinstating non-drug reward responsiveness. This motivates further work to examine the therapeutic potential of cognitive neurostimulation in CUD.

neuroscience↗