bims-mitran 2022-06-26 papers

Issue of 2022–06–26
three papers selected by
Andreas Kohler, Stockholm University

Biochim Biophys Acta Mol Basis Dis. 2022 Jun 15. pii: S0925-4439(22)00138-7. [Epub ahead of print] 166467

Disease causing mutation (P178L) in mitochondrial transcription factor A results in impaired mitochondrial transcription initiation.

Majda Mehmedović, Martial Martucci, Henrik Spåhr, Layal Ishak, Anup Mishra, Maria Eugenia Sanchez-Sandoval, Carlos Pardo-Hernández, Bradley Peter, Siet M van den Wildenberg, Maria Falkenberg, Geraldine Farge.

Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression, and packaging of mitochondrial DNA (mtDNA). Recently, a pathogenic homozygous variant in TFAM (P178L) has been associated with a severe mtDNA depletion syndrome leading to neonatal liver failure and early death. We have performed a biochemical characterization of the TFAM variant P178L in order to understand the molecular basis for the pathogenicity of this mutation. We observe no effects on DNA binding, and compaction of DNA is only mildly affected by the P178L amino acid change. Instead, the mutation severely impairs mtDNA transcription initiation at the mitochondrial heavy and light strand promoters. Molecular modeling suggests that the P178L mutation affects promoter sequence recognition and the interaction between TFAM and the tether helix of POLRMT, thus explaining transcription initiation deficiency.

Keywords: Disease causing mutation; Mitochondria; TFAM; Transcription initiation; mtDNA depletion

DOI: https://doi.org/10.1016/j.bbadis.2022.166467

Sci Rep. 2022 Jun 23. 12(1): 10658

Expression and prognosis analysis of mitochondrial ribosomal protein family in breast cancer.

Xiaoyi Lin, Lijuan Guo, Xin Lin, Yulei Wang, Guochun Zhang.

Breast cancer (BC) is characterized by high morbidity. Mitochondrial ribosomal protein (MRP) family participates in mitochondrial energy metabolism, underlying BC progression. This study aims to analyze the expression and prognosis effect of the MRP genes in BC patients. GEPIA2, UALCAN, cBioPortal, and MethSurv were used to demonstrate the differential expression, genomic alteration profiles, and DNA methylation of the MRP gene family in BC. Functional enrichment analysis and protein-protein interaction network construction were performed to understand the biological function. Based on 1056 TCGA samples with the transcriptional level of MRPs, Kaplan-Meier curves, Cox, and LASSO regression were applied to explore their prognostic effects. 12 MRPs were upregulated in BC, which were associated with gene amplification and DNA methylation. MRP genetic alteration occurred in 42% of BC patients, and amplification was the most frequent variation. Functioning in its entirety, the MRP family was involved in mitochondrial translational termination, elongation, translation, and poly(A) RNA binding. High expression of MRPL1, MRPL13, MRPS6, MRPS18C, and MRPS35, as well as low levels of MRPL16, and MRPL40 significantly indicated poor prognosis in BC patients. Thus, a novel MRP-based prognostic nomogram was established and verified with favorable discrimination and calibration. We not only provided a thorough expression and prognosis analysis of the MRP family in BC patients but also constructed an MRP-based prognostic nomogram. It was suggested that MRPs acted as biomarkers in individualized risk prediction and may serve as potential therapeutic targets in BC patients.

DOI: https://doi.org/10.1038/s41598-022-14724-7