A5059776722- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- RNA and protein synthesis mechanisms
- Metabolism and Genetic Disorders
- Photosynthetic Processes and Mechanisms
- RNA modifications and cancer
- DNA Repair Mechanisms
- Metalloenzymes and iron-sulfur proteins
- Ubiquitin and proteasome pathways
- Sirtuins and Resveratrol in Medicine
- Tryptophan and brain disorders
- Folate and B Vitamins Research
- Metal-Catalyzed Oxygenation Mechanisms
- Muscle Physiology and Disorders
- Bacterial Genetics and Biotechnology
- Hereditary Neurological Disorders
- Autophagy in Disease and Therapy
- Porphyrin Metabolism and Disorders
- Nutrition and Health in Aging
- interferon and immune responses
- Protein Tyrosine Phosphatases
- Retinoids in leukemia and cellular processes
- Biochemical effects in animals
- Electrocatalysts for Energy Conversion
- Endoplasmic Reticulum Stress and Disease
University of Helsinki
2012-2024
Planmed (Finland)
2023
Institute for Molecular Medicine Finland
2014
University of Turku
2014
Broad Institute
2014
Massachusetts General Hospital
2014
Helsinki University Hospital
2011
Michigan State University
2011
Imaging Center
2011
Abstract Nutrient availability is the major regulator of life and reproduction, a complex cellular signaling network has evolved to adapt organisms fasting. These sensor pathways monitor energy metabolism, especially mitochondrial ATP production NAD + / NADH ratio, as signals for nutritional state. We hypothesized that these would be modified by respiratory chain disease, because inefficient utilization production. Oral administration nicotinamide riboside ( NR ), vitamin B3 precursor, was...
Next-generation sequencing has turned out to be a powerful tool uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the (tRNA) synthetase (mtPheRS) two patients with fatal epileptic encephalopathy. The affected highly conserved amino acids, p.I329T p.D391V. Recently, homozygous variant p.Y144C was reported Saudi girl...
Electron transfer in complex I from Escherichia coli was investigated by an ultrafast freeze-quench approach. The reaction of with NADH stopped the time domain 90 μs to 8 ms and analyzed electron paramagnetic resonance (EPR) spectroscopy at low temperatures. data show that after binding first molecule NADH, two electrons move via FMN cofactor iron–sulfur (Fe/S) centers N1a N2 apparent constant ≈90 μs, implying these should have highest redox potential enzyme. rate reduction center (the last...
<h3>Background</h3> The genetic complexity of infantile cardiomyopathies is remarkable, and the importance mitochondrial translation defects as a causative factor only starting to be recognised. We investigated basis for onset recessive hypertrophic cardiomyopathy in two siblings. <h3>Methods results</h3> Analysis respiratory chain enzymes revealed combined deficiency complexes I IV heart skeletal muscle. Exome sequencing uncovered homozygous mutation (L156R) <i>MRPL44</i> both encodes...
De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified dominantly inherited heterozygous variant c.1064G > A (p.G355D) mother presenting hereditary spastic paraplegia (HSP) neuropathy her son dyskinetic cerebral palsy, both disease onset childhood. HSP is...
Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations the tricarboxylic acid cycle (TCA) gene subunit-β (SUCLA2), causing global hyper-succinylation. Using mass spectrometry, quantify nearly 1,000 succinylation sites on 366 proteins...
The accuracy of mitochondrial protein synthesis is dependent on the coordinated action nuclear-encoded aminoacyl-tRNA synthetases (mtARSs) and DNA-encoded tRNAs. recent advances in whole-exome sequencing have revealed importance mtARS proteins for pathophysiology since nearly every nuclear gene (out 19) now recognized as a disease disease. Typically, defects each been identified one tissue-specific disease, most commonly affecting brain, or syndrome. However, mutations AARS2 alanyl-tRNA...
Abstract Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying clinical variability remain poorly understood. To clarify whether brain cells have differential sensitivity to mitochondrial dysfunction, we induced DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), replicative mtDNA helicase. Here show that astrocytes, most abundant cerebral cell type, are chronically activated upon loss, leading...
Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of child manifesting at one month age and progressing to death by 2.4 years, identified novel compound heterozygous variants in PNPT1, encoding polynucleotide phosphorylase (PNPase). Expression wild type PNPT1 subject's myoblasts functionally complemented defects, pathogenicity was further supported structural predictions protein RNA analyses. PNPase key enzyme...
Argininosuccinate lyase deficiency (ASLD) is a recessive metabolic disorder caused by variants in ASL. In an essential step urea synthesis, ASL breaks down argininosuccinate (ASA), pathognomonic ASLD biomarker. The severe disease forms lead to hyperammonemia, neurological injury, and even early death. current treatments are unsatisfactory, involving strict low-protein diet, arginine supplementation, nitrogen scavenging, some cases, liver transplantation. An unmet need exists for improved,...
Objective: Mitochondrial DNA polymerase γ ( POLG1 ) mutations in children often manifest as Alpers syndrome, whereas adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy. Because some patients MIRAS have presented or epilepsy already childhood, we searched for neurologic manifestations childhood. Methods: We investigated 136 children, all clinically suspected to disease, one more of the following: ataxia, axonal neuropathy, without known...
The redox properties of the cofactors NADH:ubiquinone oxidoreductase (complex I) from Escherichia coli were studied by following changes in electron paramagnetic resonance (EPR) and optical spectra upon electrochemical titration purified protein. At neutral pH, FMN cofactor had a midpoint potential (Em) ∼ −350 mV (n = 2). Binuclear FeS clusters well-characterized: N1a was titrated with single 1) transition, Em −235 mV. In contrast, N1b can only be fitted sum at least two one-electron...
We report novel defects of mitochondrial translation elongation factor Ts (EFTs), with high carrier frequency in Finland and expand the manifestations this disease group from infantile cardiomyopathy to juvenile neuropathy/encephalopathy disorders.DNA analysis, whole-exome protein biochemistry, modeling.We used sequencing find genetic cause infantile-onset cardiomyopathy, progressing juvenile-onset Leigh syndrome, neuropathy, optic atrophy 2 siblings. found compound heterozygous mutations,...
Isolated defects of the mitochondrial respiratory complex II (succinate dehydrogenase, SDH) are rare, accounting for approximately 2% all chain deficiency diagnoses. Here, we report clinical and molecular investigations three family members with a heterozygous mutation in large flavoprotein subunit SDHA previously described to cause deficiency. The index patient presented bilateral optic atrophy ocular movement disorder, progressive polyneuropathy, psychiatric involvement, cardiomyopathy....
Accuracy of protein synthesis is enabled by the selection amino acids for tRNA charging aminoacyl-tRNA synthetases (ARSs), and further enhanced proofreading functions some these enzymes eliminating tRNAs mischarged with noncognate acids. Mouse models editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated importance synthesis, embryonic lethal progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set nuclear-encoded ARSs...
Mitochondria are central organelles to cellular metabolism. Their function relies largely on nuclear-encoded proteins that must be imported from the cytosol, and thus protein import pathways important for maintenance of mitochondrial proteostasis. Mitochondrial HSP70 (mtHsp70) is a key component in facilitating translocation through inner membrane into matrix. Its folding cycle regulated by nucleotide-exchange factor GrpE, which triggers release folded ATP rebinding. Vertebrates have two...
Cancer cachexia and muscle loss are associated with increased morbidity mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival prevented wasting in cancer without an effect on tumour growth. However, the underlying mechanisms poorly understood. This study aimed to identify soluble ACVR (sACVR) administration-evoked changes proteome.Healthy C26 tumour-bearing (TB) mice were treated recombinant sACVR. The sACVR or PBS control administered either...
Nicotinamide adenine dinucleotide (NAD) and glutathione are vital molecules that control redox-state, enzyme functions metabolic flux in hundreds of cellular reactions. High NAD+ level occurs fasting has been associated with health outcomes model systems, while low NAD+/NADH ratio specific diseases. Still, the normal, booster-treated or disease-related levels NADs glutathiones not well known humans. Here, we present a standardized technology for high-throughput quantitative measurement NAD+,...
Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most variants aggregation CHCHD10 activation proteotoxic stress responses, the pathogenic mechanisms variant are less clear. Here we report first homozygous patient, show that dosage dictates...