bims-cytox1 2021-01-24 papers

Issue of 2021‒01‒24
three papers selected by
Gavin McStay
Staffordshire University

Nat Metab. 2021 Jan;3(1): 33-42

Tetracyclines promote survival and fitness in mitochondrial disease models.

Elizabeth A Perry, Christopher F Bennett, Chi Luo, Eduardo Balsa, Mark Jedrychowski, Katherine E O'Malley, Pedro Latorre-Muro, Richard Porter Ladley, Kamar Reda, Peter M Wright, Steven P Gygi, Andrew G Myers, Pere Puigserver.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from mutations in nuclear or mitochondrial DNA genes encoding mitochondrial proteins1,2. MDs cause pathologies with severe tissue damage and ultimately death3,4. There are no cures for MDs and current treatments are only palliative5-7. Here we show that tetracyclines improve fitness of cultured MD cells and ameliorate disease in a mouse model of Leigh syndrome. To identify small molecules that prevent cellular damage and death under nutrient stress conditions, we conduct a chemical high-throughput screen with cells carrying human MD mutations and discover a series of antibiotics that maintain survival of various MD cells. We subsequently show that a sub-library of tetracycline analogues, including doxycycline, rescues cell death and inflammatory signatures in mutant cells through partial and selective inhibition of mitochondrial translation, resulting in an ATF4-independent mitohormetic response. Doxycycline treatment strongly promotes fitness and survival of Ndufs4-/- mice, a preclinical Leigh syndrome mouse model8. A proteomic analysis of brain tissue reveals that doxycycline treatment largely prevents neuronal death and the accumulation of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causal role for these proteins in the brain pathology. Our findings suggest that tetracyclines deserve further evaluation as potential drugs for the treatment of MDs.

DOI: https://doi.org/10.1038/s42255-020-00334-y

J Clin Invest. 2021 Jan 19. pii: 138267. [Epub ahead of print]

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

Sarah L Stenton, Natalia L Sheremet, Claudia B Catarino, Natalia Andreeva, Zahra Assouline, Piero Barboni, Ortal Barel, Riccardo Berutti, Igor O Bychkov, Leonardo Caporali, Mariantonietta Capristo, Michele Carbonelli, Maria Lucia Cascavilla, Peter Charbel Issa, Peter Freisinger, Sylvie Gerber, Daniele Ghezzi, Elisabeth Graf, Juliana Heidler, Maja Hempel, Elise Heon, Yulia S Itkis, Elisheva Javasky, Josseline Kaplan, Robert Kopajtich, Cornelia Kornblum, Reka Kovacs-Nagy, Tatiana Krylova, Wolfram S Kunz, Chiara La Morgia, Costanza Lamperti, Christina Ludwig, Pedro F Malacarne, Alessandra Maresca, Johannes A Mayr, Jana Meisterknecht, Tatiana Nevinitsyna, Flavia Palombo, Ben Pode-Shakked, Maria S Shmelkova, Tim M Strom, Francesca Tagliavini, Michal Tzadok, Amelie T van der Ven, Catherine Vignal-Clermont, Matias Wagner, Ekaterina Zakharova, Nino Zhorzholadze, Jen-Michel Rozet, Valerio Carelli, Polina Tsygankova, Thomas Klopstock, Ilka Wittig, Holger Prokisch.

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in the mitochondrial DNA (mtDNA). A molecular diagnosis is reached in up to 95%, the vast majority of which are accounted for by three mutations within mitochondrial complex I (CI) subunit encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON are recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knock-out cellular model, we measure reduced turnover of specific CI N-module subunits and a resultant impairment of CI function. This demonstrates DNAJC30 is to be a chaperone protein needed for the efficient exchange of CI subunits exposed to reactive oxygen species and integral to a mitochondrial CI repair mechanism, thereby providing the first example of a disease resulting from impaired exchange of assembled respiratory chain subunits.

Keywords: Genetic diseases; Genetics; Neuroscience

DOI: https://doi.org/10.1172/JCI138267

J Neurol. 2021 Jan 23.

Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

Sanjiban Chakrabarty, Periyasamy Govindaraj, Bindu Parayil Sankaran, Madhu Nagappa, Shama Prasada Kabekkodu, Pradyumna Jayaram, Sandeep Mallya, Sekar Deepha, J N Jessiena Ponmalar, Hanumanthapura R Arivinda, Angamuthu Kanikannan Meena, Rajan Kumar Jha, Sanjib Sinha, Narayanappa Gayathri, Arun B Taly, Kumarasamy Thangaraj, Kapaettu Satyamoorthy.

BACKGROUND: Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation.METHODS: The clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations.
RESULTS: Analysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation.
CONCLUSION: Individuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.

Keywords: CNV; MELAS; Mutations; Nuclear genome; mtDNA

DOI: https://doi.org/10.1007/s00415-020-10390-9