TY  - JOUR
AB  - AIM: To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineural hearing loss, without clear evidence of progressive external ophthalmoplegia. METHODS: Several genetic tests were performed over the years including single-gene sequencing, mitochondrial DNA (mtDNA) sequencing, NGS panel for mitochondrial diseases and cardiomyopathies, clinical exome sequencing and whole exome sequencing. Specific amplifications and long-read NGS were used to evaluate mtDNA structural alterations. RESULTS: By means whole exome sequencing we found a novel heteroplasmic 12 kb-long single deletion in the mtDNA in all affected family members, confirmed by long-range PCR. However, a deeper investigation by long-read NGS revealed indeed the presence of rearranged mtDNA species, formed by a wild-type plus a deleted molecule. This mtDNA duplication turned out to be inherited in our pedigree and present in all tested specimens. CONCLUSION: While mtDNA single large-scale deletions are generally considered sporadic, few old reports described maternally inherited mtDNA duplication We suggest that mtDNA large rearrangements should be considered as possible disease causes in familial cases with unusual mitochondrial phenotypes. Long-read sequencing is useful for the detection of these variants, particularly mtDNA duplications.
AU  - Lopriore, P.*
AU  - Legati, A.*
AU  - Neuhofer, C.
AU  - Gerfo, A.L.*
AU  - Kopajtich, R.
AU  - Barresi, M.*
AU  - Cecchi, G.*
AU  - Pavlov, M.
AU  - Izzo, R.*
AU  - Montano, V.*
AU  - Caligo, M.A.*
AU  - Berutti, R.
AU  - Mancuso, M.*
AU  - Prokisch, H.
AU  - Ghezzi, D.*
C1  - 73922
C2  - 57242
CY  - 125 London Wall, London, England
TI  - An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary cardiological phenotype.
JO  - Mitochondrion
VL  - 83
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - Leigh syndrome (LS) is one of the most common mitochondrial diseases in children, for which at least 90 causative genes have been identified. However, many LS patients have no genetic diagnosis, indicating that more disease-related genes remain to be identified. In this study, we identified a novel variant, m.3955G > A, in mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in two unrelated LS patients, manifesting as infancy-onset frequent seizures, neurodegeneration, elevated lactate levels, and bilateral symmetrical lesions in the brainstem, basal ganglia, and thalamus. Transfer of the mutant mtDNA with m.3955G > A into cybrids disturbed the MT-ND1 expression and CI assembly, followed by remarkable mitochondrial dysfunction, reactive oxygen species production, and mitochondrial membrane potential reduction. Our findings demonstrated the pathogenicity of the novel m.3955G > A variant, and extend the spectrum of pathogenic mtDNA variants.
AU  - Xu, M.*
AU  - Kopajtich, R.
AU  - Elstner, M.*
AU  - Li, H.*
AU  - Liu, Z.*
AU  - Wang, J.*
AU  - Prokisch, H.
AU  - Fang, F.*
C1  - 63479
C2  - 51548
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 13-23
TI  - Identification of a novel m.3955G > A variant in MT-ND1 associated with Leigh syndrome.
JO  - Mitochondrion
VL  - 62
PB  - Elsevier Sci Ltd
PY  - 2022
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - Western lifestyle-associated malnutrition causes steatosis that may progress to liver inflammation and mitochondrial dysfunction has been suggested as a key factor in promoting this disease. Here we have molecularly, biochemically and biophysically analyzed mitochondria from steatotic wild type and immune-compromised mice fed a Western diet (WD) - enriched in saturated fatty acids (SFAs). WD-mitochondria demonstrated lipidomic changes, a decreased mitochondrial ATP production capacity and a significant sensitivity to calcium. These changes preceded hepatocyte damage and were not associated with enhanced ROS production. Thus, WD-mitochondria do not promote steatohepatitis per se, but demonstrate bioenergetic deficits and increased sensitivity to stress signals.
AU  - Einer, C.
AU  - Hohenester, S.*
AU  - Wimmer, R.*
AU  - Wottke, L.*
AU  - Artmann, R.*
AU  - Schulz, S.
AU  - Gosmann, C.
AU  - Simmons, A.
AU  - Leitzinger, C.
AU  - Eberhagen, C.
AU  - Borchard, S.
AU  - Schmitt, S.*
AU  - Hauck, S.M.
AU  - von Toerne, C.
AU  - Jastroch, M.
AU  - Walheim, E.
AU  - Rust, C.*
AU  - Gerbes, A.L.*
AU  - Popper, B.*
AU  - Mayr, D.*
AU  - Schnurr, M.*
AU  - Vollmar, A.M.*
AU  - Denk, G.U.*
AU  - Zischka, H.
C1  - 51959
C2  - 43613
TI  - Mitochondrial adaptation in steatotic mice.
JO  - Mitochondrion
PY  - 2018
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chaperone for the Rieske iron‑sulfur (Fe-S) protein in the mitochondrial matrix. Using exome sequencing, we identified homozygosity for a splice site destroying 4 base pair deletion in LYRM7 in a child with recurrent lactic acidotic crises and distinct early-onset leukencephalopathy. Sanger sequencing showed variant segregation in similarly affected family members. Functional analyses revealed a reduced amount of the Rieske Fe-S protein, which was restored after re-expression of LYRM7. Our data provide further evidence for the importance of LYRM7 for mitochondrial function and emphasise the importance of whole exome sequencing in the diagnosis of rare mitochondrial diseases.
AU  - Hempel, M.*
AU  - Kremer, L.S.
AU  - Tsiakas, K.*
AU  - Alhaddad, B.*
AU  - Haack, T.B.
AU  - Löbel, U.*
AU  - Feichtinger, R.G.*
AU  - Sperl, W.*
AU  - Prokisch, H.
AU  - Mayr, J.A.*
AU  - Santer, R.*
C1  - 51508
C2  - 43274
CY  - Oxford
SP  - 55-61
TI  - LYRM7 - associated complex III deficiency: A clinical, molecular genetic, MR tomographic, and biochemical study.
JO  - Mitochondrion
VL  - 37
PB  - Elsevier Sci Ltd
PY  - 2017
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - 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.14484T>C heteroplasmic. The unusually low male-to-female ratio of affected family members is also seen among the other patients previously reported with two primary LHON mutations m.11778G>A and m.14484T>C. While the index patient had very late onset of symptoms at 75years and severe visual loss, her two daughters had both onset in childhood (6 and 9years), with moderate to mild visual loss. A higher degree of heteroplasmy of the m.14484T>C mutation was found to correlate with an earlier age at onset in this family. Ours is the first LHON family harboring two primary LHON mutations where functional studies were performed in several affected family members. A more pronounced bioenergetic defect was found to correlate with an earlier age at onset. The patient with the earliest age at onset had a more significant complex I dysfunction than all controls, including the LHON patient with only the m.11778G>A mutation, suggesting a synergistic effect of the two primary LHON mutations in this patient.
AU  - Catarino, C.B.*
AU  - Ahting, U.*
AU  - Gusic, M.
AU  - Iuso, A.
AU  - Repp, B.
AU  - Peters, K.*
AU  - Biskup, S.*
AU  - von Livonius, B.*
AU  - Prokisch, H.
AU  - Klopstock, T.*
C1  - 49701
C2  - 40865
CY  - Oxford
SP  - 15-20
TI  - Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA.
JO  - Mitochondrion
VL  - 36
PB  - Elsevier Sci Ltd
PY  - 2016
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - It has been suggested that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To test whether mitochondrial variants influence the risk of asthma, we analyzed 16,158 mtSNPs in a sample of 372 asthmatic children and 395 healthy children using the DNA pooling technique and genome wide association analysis. Stratified analysis by sex was performed to explain the differences observed between sexes in the etiology of asthma. Different variants were detected to be significant in the sample of girls and boys with the smallest adjusted P values being 1.4x10(-09) (mt5295) and 3.6x10(-12) (mt16158), respectively. Most of the significant locations found in boys are within the CYB gene and the non-coding region. For girls, most of the significant mtSNPs lie within NADH-dehydrogenase-subunits. The variants reported here have not previously been described in connection with asthma. Although further studies in other cohorts are needed to confirm these findings our study highlights the importance of the mitochondria among the factors that contribute to the risk of asthma.
AU  - Flaquer, A.
AU  - Heinzmann, A.*
AU  - Rospleszcz, S.
AU  - Mailaparambil, B.*
AU  - Dietrich, H.*
AU  - Strauch, K.
AU  - Grychtol, R.*
C1  - 28490
C2  - 33424
CY  - Oxford
SP  - 49-53
TI  - Association study of mitochondrial genetic polymorphisms in asthmatic children.
JO  - Mitochondrion
VL  - 14
IS  - 1
PB  - Elsevier Science
PY  - 2014
SN  - 1567-7249
ER  - 

TY  - JOUR
AB  - Prompted by pronounced structural differences between rat liver and rat hepatocellular carcinoma mitochondria, we suspected these mitochondrial populations to differ massively in their molecular composition. Aiming to reveal these mitochondrial differences, we came across the issue on how to normalize such comparisons and decided to focus on the absolute number of mitochondria. To this end, fluorescently stained mitochondria were quantified by flow cytometry. For rat liver mitochondria, this approach resulted in mitochondrial protein contents comparable to earlier reports using alternative methods. We determined similar protein contents for rat liver, heart and kidney mitochondria. In contrast, however, lower protein contents were determined for rat brain mitochondria and for mitochondria from the rat hepatocellular carcinoma cell line McA 7777. This result challenges mitochondrial comparisons that rely on equal protein amounts as a typical normalization method. Exemplarily, we therefore compared the activity and susceptibility towards inhibition of complex II of rat liver and hepatocellular carcinoma mitochondria and obtained significant discrepancies by either normalizing to protein amount or to absolute mitochondrial number. Importantly, the latter normalization, in contrast to the former, demonstrated a lower complex II activity and higher susceptibility towards inhibition in hepatocellular carcinoma mitochondria compared to liver mitochondria. These findings demonstrate that solely normalizing to protein amount may obscure essential molecular differences between mitochondrial populations.
AU  - Schmitt, S.
AU  - Schulz, S.
AU  - Schropp, E.-M.
AU  - Eberhagen, C.
AU  - Simmons, A.
AU  - Beisker, W.
AU  - Aichler, M.
AU  - Zischka, H.
C1  - 31695
C2  - 34680
SP  - 113-123
TI  - Why to compare absolute numbers of mitochondria.
JO  - Mitochondrion
VL  - 19
PY  - 2014
SN  - 1567-7249
ER  - 

TY  - JOUR
AU  - Mueller, J.C.
AU  - Andreoli, C.
AU  - Prokisch, H.
AU  - Meitinger, T.
C1  - 3668
C2  - 21775
SP  - 315-325
TI  - Mechanisms for multiple intracellular localization of human mitochondrial proteins.
JO  - Mitochondrion
VL  - 3
PY  - 2004
SN  - 1567-7249
ER  -