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Sanchez E.,Hospital Universitario Miguel Servet | Lobo T.,Hospital Universitario Miguel Servet | Fox J.L.,University of Utah | Fox J.L.,College of Charleston | And 4 more authors.
Biochimica et Biophysica Acta - Bioenergetics

The mammalian Complex III (CIII) assembly process is yet to be completely understood. There is still a lack in understanding of how the structural subunits are put together and which additional factors are involved. Here we describe the identification and characterization of LYRM7, a human protein displaying high sequence homology to the Saccharomyces cerevisiae protein Mzm1, which was recently shown as an assembly factor for Rieske Fe-S protein incorporation into the yeast cytochrome bc1 complex. We conclude that human LYRM7, which we propose to be renamed MZM1L (MZM1-like), works as a human Rieske Fe-S protein (UQCRFS1) chaperone, binding to this subunit within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane. Thus, LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 insertion step, which enables formation of the mature and functional CIII enzyme. © 2012 Elsevier B.V. Source

Invernizzi F.,Unit of Molecular Neurogenetics | Ardissone A.,Unit of Child Neurology | Lamantea E.,Unit of Molecular Neurogenetics | Garavaglia B.,Unit of Molecular Neurogenetics | And 4 more authors.
Frontiers in Genetics

Multiple Mitochondrial Dysfunction Syndrome (MMDS) comprises a group of severe autosomal recessive diseases with onset in early infancy and characterized by a systemic disorder of energy metabolism, resulting in weakness, respiratory failure, lack of neurological development, lactic acidosis, and early death. Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc). Three genes have been associated with MMDS since now: NFU1, BOLA3, and IBA57. We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity. He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues. A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene. © 2014 Invernizzi, Ardissone, Lamantea, Garavaglia, Zeviani, Farina, Ghezzi and Moroni. Source

Alsaman A.,King Fahad Medical City | Tomoum H.,King Fahad Medical City | Tomoum H.,Ain Shams University | Invernizzi F.,Unit of Molecular Neurogenetics | Zeviani M.,Unit of Molecular Neurogenetics
Saudi Journal of Gastroenterology

Mitochondrial DNA depletion syndromes (MDSs) are autosomal recessive diseases characterized by a severe decrease in mitochondrial DNA content leading to dysfunction of the affected organ. Autosomal recessive mutations in MPV17 have been identified in the hepatocerebral form of MDS. We describe the clinical features, biochemical and molecular results of a Saudi infant with a new mutation of MPV17 and compared the features to those of previously reported cases. We stress the importance of such rare cases particularly in countries with high consanguineous marriage rate. Source

Deepa S.S.,University of Texas Health Science Center at San Antonio | Pulliam D.,University of Texas Health Science Center at San Antonio | Hill S.,University of Texas Health Science Center at San Antonio | Shi Y.,University of Texas Health Science Center at San Antonio | And 11 more authors.
FASEB Journal

Mice lacking Surf1, a complex IV assembly protein, have 50-70% reduction in cytochrome c oxidase activity in all tissues yet a paradoxical increase in lifespan. Here we report that Surf1-/- mice have lower body (15%) and fat (20%) mass, in association with reduced lipid storage, smaller adipocytes, and elevated indicators of fatty acid oxidation in white adipose tissue (WAT) compared with control mice. The respiratory quotient in the Surf1-/- mice was significantly lower than in the control animals (0.83- 0.93 vs. 0.90-0.98), consistent with enhanced fat utilization in Surf1-/- mice. Elevated fat utilization was associated with increased insulin sensitivity measured as insulinstimulated glucose uptake, as well as an increase in insulin receptor levels (2-fold) and glucose transporter type 4 (GLUT4; 1.3-fold) levels in WAT in the Surf1-/- mice. The expression of peroxisome proliferator- activated receptor β-coactivator 1 (PGC-1α) mRNA and protein was up-regulated by 2.5- and 1.9- fold, respectively, in WAT from Surf1-/- mice, and the expression of PGC-1α target genes and markers of mitochondrial biogenesis was elevated. Together, these findings point to a novel and unexpected link between reduced mitochondrial complex IV activity, enhanced insulin sensitivity, and increased mitochondrial biogenesis that may contribute to the increased longevity in the Surf1-/- mice.-Deepa, S. S., Pulliam, D., Hill, S., Shi, Y., Walsh, M. E., Salmon, A., Sloane, L., Zhang, N., Zeviani, M., Viscomi, C., Musi, N., Van Remmen, H. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J. 27, 1371-1380 (2013). www.fasebj.org. Source

Invernizzi F.,Unit of Molecular Neurogenetics | Tigano M.,University of Parma | Dallabona C.,University of Parma | Donnini C.,University of Parma | And 6 more authors.
Human Mutation

Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1Δ yeast strain, the expression of a mzm1D25N mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe-S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy. We report the first patient affected by an infantile mitochondrial disease caused by a mutation in LYRM7. The patient displayed severe complex III deficiency, associated with early-onset lactic acidosis and rapidly progressive encephalopathy. © 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc. Source

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