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Mitochondrial disease complex I

Anne S Bie, Paula Fernandez-Guerra, Rune I D Birkler, Shahar Nisemblat, Dita Pelnena, Xinping Lu, Joshua L Deignan, Hane Lee, Naghmeh Dorrani, Thomas J Corydon, Johan Palmfeldt, Liga Bivina, Abdussalam Azem, Kristin Herman, Peter Bross
We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature...
2016: Frontiers in Molecular Biosciences
Jonathan Boyd, Alice Han
Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson's disease (PD)...
2016: Advances in Experimental Medicine and Biology
M I Alvarez-Mora, L Rodriguez-Revenga, I Madrigal, M Guitart-Mampel, G Garrabou, M Milà
Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a FMR1 premutation (55-200 CGG repeats) are at risk of presenting an adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity...
October 22, 2016: Molecular Neurobiology
Stepana Boukalova, Jan Stursa, Lukas Werner, Zuzana Ezrova, Jiri Cerny, Ayenachew Bezawork-Geleta, Alena Pecinova, Lanfeng Dong, Zdenek Drahota, Jiri Neuzil
Pancreatic cancer is one of the hardest-to-treat types of neoplastic diseases. Metformin, a widely prescribed drug against type 2 diabetes mellitus, is being trialed as an agent against pancreatic cancer, although its efficacy is low. With the idea of delivering metformin to its molecular target, the mitochondrial complex I (CI), we tagged the agent with the mitochondrial vector, triphenylphosphonium group. Mitochondrially targeted metformin (MitoMet) was found to kill a panel of pancreatic cancer cells 3-4 orders of magnitude more efficiently than found for the parental compound...
October 7, 2016: Molecular Cancer Therapeutics
Xianxiu Wan, Jian-Jun Wen, Sue-Jie Koo, Lisa Yi Liang, Nisha Jain Garg
Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease...
October 2016: PLoS Pathogens
Bing Xu, Xiyuan Li, Miaomiao Du, Chao Zhou, Hezhi Fang, Jianxin Lyu, Yanling Yang
By using next-generation sequencing targeted to MitoExome including the entire mtDNA and exons of 1033 genes encoding the mitochondrial proteome, we described here a novel m.11240C>T mutation in the mitochondrial ND4 gene from a patient with Leigh syndrome. High mutant loads of m.11240C>T were detected in blood, urinary epithelium, oral mucosal epithelium cells, and skin fibroblasts of the patient. Decreased mitochondrial complex I activity was found in transmitochondrial cybrids containing the m.11240C>T mutation with biochemical analysis...
October 20, 2016: Journal of Human Genetics
Michel van Schaardenburgh, Martin Wohlwend, Øivind Rognmo, Erney J R Mattsson
PURPOSE: Mitochondria are essential for energy production in the muscle cell and for this they are dependent upon a sufficient supply of oxygen by the circulation. Exercise training has shown to be a potent stimulus for physiological adaptations and mitochondria play a central role. Whether changes in mitochondrial respiration are seen after exercise in patients with a reduced circulation is unknown. The aim of the study was to evaluate the time course and whether one session of calf raise exercise stimulates mitochondrial respiration in the calf muscle of patients with peripheral vascular disease...
2016: PloS One
Ahmad Alodaib, Nara Sobreira, Wendy A Gold, Lisa G Riley, Nicole J Van Bergen, Meredith J Wilson, Bruce Bennetts, David R Thorburn, Corinne Boehm, John Christodoulou
Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals...
October 19, 2016: European Journal of Human Genetics: EJHG
Cinzia Nasuti, Gloria Brunori, Piera Eusepi, Lisa Marinelli, Roberto Ciccocioppo, Rosita Gabbianelli
INTRODUCTION: Oxidative stress, alpha-synuclein changes, mitochondrial complex I defects and dopamine loss, observed in the striatum of rats exposed to the pesticide permethrin in early life, could represent neuropathological hallmarks of Parkinson's disease (PD). Nevertheless, an animal model of PD should also fulfill criteria of face and predictive validities. This study was designed to: 1) verify dopaminergic status in the striatum and substantia nigra pars compacta; 2) recognize non-motor symptoms; 3) investigate the time-course development of motor disabilities; 4) assess L-Dopa effectiveness on motor symptoms in rats previously exposed to permethrin in early life...
October 15, 2016: Journal of Pharmacological and Toxicological Methods
Kazumasa Fuwa, Mitsuru Kubota, Masami Kanno, Hiroshi Miyabayashi, Ken Kawabata, Keiichi Kanno, Masaki Shimizu
Diagnosis of mitochondrial respiratory chain disorder (MRCD) is often difficult. Its pathogenesis is still unclear. We diagnosed MRCD by measuring the activity of the mitochondrial respiratory chain enzyme, and the patient also had hemophagocytic lymphohistiocytosis (HLH). A preterm female infant was born at 34 weeks of gestation. On day 6, HLH was revealed by bone marrow aspiration. She died on day 10 due to uncontrollable HLH. An autopsy was performed, and we measured the activity of the mitochondrial respiratory chain enzyme in the liver, muscle, and heart...
2016: Case Reports in Pediatrics
Jian-Jun Wen, Xianxiu Wan, John Thacker, Nisha Jain Garg
BACKGROUND: Chagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM. METHODS AND RESULTS: C57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks...
June 2016: JACC. Basic to Translational Science
Adrienne Wang, Jacob Mouser, Jason Pitt, Daniel Promislow, Matt Kaeberlein
Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS...
October 11, 2016: Oncotarget
Takashi Owada, Hiroyuki Yamauchi, Shu-Ichi Saitoh, Shunsuke Miura, Hirofumi Machii, Yasuchika Takeishi
BACKGROUND: Senescence is a major factor that increases oxidative stress in mitochondria, which contributes toward the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive. OBJECTIVES: We postulated that the mitochondrial targeting of superoxide scavenging would have benefits in the aged heart. METHODS AND RESULTS: Generation of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity increased in the heart of old mice compared with that in young mice...
October 12, 2016: Coronary Artery Disease
Nivedita Bhattacharjee, Anupom Borah
Homocysteine (Hcy) when injected intranigrally in rat caused parkinsonian behavioural phenotypes and loss of nigral dopaminergic neurons but the underlying mechanisms of neurotoxicity remains elusive. In the present study, we focused on oxidative stress as one of the mechanisms of neurotoxicity in Hcy-induced hemiparkinsonian rat model. Unilateral intranigral infusion of Hcy (1.0 μmol in 2 μl) caused inhibition of mitochondrial complex-I activity, decrease in the level of striatal dopamine, loss of midbrain dopaminergic neurons, and motor abnormalities...
October 9, 2016: Neurochemistry International
Meredith Meyer, Attila D Kovács, David A Pearce
Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1 (-/-) ) mice, a model of infantile CLN1 disease...
October 8, 2016: Metabolic Brain Disease
Claudia B Catarino, Uwe Ahting, Mirjana Gusic, Arcangela Iuso, Birgit Repp, Katrin Peters, Saskia Biskup, Bettina von Livonius, Holger Prokisch, Thomas Klopstock
Leber's hereditary optic neuropathy (LHON) is an inherited mitochondrial disease that usually leads to acute or subacute bilateral central vision loss. In 95% of cases, LHON is caused by one of three primary mutations of the mitochondrial DNA (mtDNA), m.11778G>A in the MT-ND4 gene, m.14484T>C in the MT-ND6 gene, or m.3460G>A in the MT-ND1 gene. Here we characterize clinically, genetically, and biochemically a LHON family with multiple patients harboring two of these primary LHON mutations, m.11778G>A homoplasmic and m...
October 6, 2016: Mitochondrion
T Tharmatha, K Gajapathy, R Ramasamy, S N Surendran
The correct identification of sand fly vectors of leishmaniasis is important for controlling the disease. Genetic, particularly DNA sequence data, has lately become an important adjunct to the use of morphological criteria for this purpose. A recent DNA sequencing study revealed the presence of two cryptic species in the Sergentomyia bailyi species complex in India. The present study was undertaken to ascertain the presence of cryptic species in the Se. bailyi complex in Sri Lanka using morphological characteristics and DNA sequences from cytochrome c oxidase subunits...
October 10, 2016: Bulletin of Entomological Research
Carlos R P Dechandt, Carlos A Couto-Lima, Luciane C Alberici
The research on mitochondrial functions in adipocytes has increasingly evidenced that mitochondria plays an important role in the onset and/or progression of obesity and related pathologies. Mitochondrial function in brown adipose tissue (BAT) has been classically assessed by measuring either the levels/activity of mitochondrial enzymes, or the respiration in isolated mitochondria. Isolation of mitochondria is not advantageous because it demands significant time and amount of tissue and, as tissue homogenates, disrupts biochemical and physical connections of mitochondria within the cell...
December 15, 2016: Analytical Biochemistry
Michael P Murphy
In this issue of Molecular Cell, Barrow et al. (2016) use two complementary approaches-one an assessment of a chemical library, and the other a genome-wide CRISPR screen-that both identify bromodomain-containing protein 4 (Brd4) as a therapeutic target for mtDNA diseases affecting complex I.
October 6, 2016: Molecular Cell
Mrigendra Bir Karmacharya, Binika Hada, So Ra Park, Byung Hyune Choi
Many studies have shown that mitochondrial dysfunction and the subsequent oxidative stress caused by excessive reactive oxygen species (ROS) generation play a central role in the pathogenesis of Parkinson's disease (PD). We have previously shown that low-intensity ultrasound (LIUS) could reduce ROS generation by L-buthionine-(S,R)-sulfoximine (BSO) in retinal pigment epithelial cells. In this study, we studied the effects of LIUS stimulation on the ROS-dependent α-synuclein aggregation in 1-methyl-4-phenylpyridinium ion (MPP(+))-treated PC12 cells...
October 6, 2016: Molecular Neurobiology
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