bims-cytox1 2019-03-03 papers

Sci Rep. 2019 Feb 28. 9(1): 3073

Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease.

Chi Fung Lee, Arianne Caudal, Lauren Abell, G A Nagana Gowda, Rong Tian.

Leigh syndrome is a mitochondrial disease characterized by neurological disorders, metabolic abnormality and premature death. There is no cure for Leigh syndrome; therefore, new therapeutic targets are urgently needed. In Ndufs4-KO mice, a mouse model of Leigh syndrome, we found that Complex I deficiency led to declines in NAD+ levels and NAD+ redox imbalance. We tested the hypothesis that elevation of NAD+ levels would benefit Ndufs4-KO mice. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN) extended lifespan of Ndufs4-KO mice and attenuated lactic acidosis. NMN increased lifespan by normalizing NAD+ redox imbalance and lowering HIF1a accumulation in Ndufs4-KO skeletal muscle without affecting the brain. NMN up-regulated alpha-ketoglutarate (KG) levels in Ndufs4-KO muscle, a metabolite essential for HIF1a degradation. To test whether supplementation of KG can treat Ndufs4-KO mice, a cell-permeable KG, dimethyl ketoglutarate (DMKG) was administered. DMKG extended lifespan of Ndufs4-KO mice and delayed onset of neurological phenotype. This study identified therapeutic mechanisms that can be targeted pharmacologically to treat Leigh syndrome.

DOI: https://doi.org/10.1038/s41598-019-39419-4

Biochim Biophys Acta Mol Cell Res. 2019 Feb 22. pii: S0167-4889(19)30021-7. [Epub ahead of print]

Mitochondrial presequence import: Multiple regulatory knobs fine-tune mitochondrial biogenesis and homeostasis.

Cyril Moulin, Anne Caumont-Sarcos, Raffaele Ieva.

Mitochondria are pivotal organelles for cellular signaling and metabolism, and their dysfunction leads to severe cellular stress. About 70% of the mitochondrial proteome consists of preproteins synthesized in the cytosol with an amino-terminal cleavable presequence targeting signal. The TIM23 complex transports presequence signals towards the mitochondrial matrix. Ultimately, the mature protein segments are either transported into the matrix or sorted to the inner membrane. To ensure accurate preprotein import into distinct mitochondrial sub-compartments, the TIM23 machinery adopts specific functional conformations and interacts with different partner complexes. Regulatory subunits modulate the translocase dynamics, tailoring the import reaction to the incoming preprotein. The mitochondrial membrane potential and the ATP generated via oxidative phosphorylation are key energy sources in driving the presequence import pathway. Thus, mitochondrial dysfunctions have rapid repercussions on biogenesis. Cellular mechanisms exploit the presequence import pathway to monitor mitochondrial dysfunctions and mount transcriptional and proteostatic responses to restore functionality.

Keywords: Mitochondrial biogenesis; Mitochondrial homeostasis; PAM; Presequence import pathway; TIM23; TOM

DOI: https://doi.org/10.1016/j.bbamcr.2019.02.012

Biochim Biophys Acta Mol Cell Res. 2019 Feb 22. pii: S0167-4889(18)30458-0. [Epub ahead of print]1866(5): 861-881

Pathophysiological characterization of MERRF patient-specific induced neurons generated by direct reprogramming.

Marina Villanueva-Paz, Suleva Povea-Cabello, Irene Villalón-García, Juan M Suárez-Rivero, Mónica Álvarez-Córdoba, Mario de la Mata, Marta Talaverón-Rey, Sandra Jackson, José A Sánchez-Alcázar.

Mitochondrial diseases are a group of rare heterogeneous genetic disorders caused by total or partial mitochondrial dysfunction. They can be caused by mutations in nuclear or mitochondrial DNA (mtDNA). MERRF (Myoclonic Epilepsy with Ragged-Red Fibers) syndrome is one of the most common mitochondrial disorders caused by point mutations in mtDNA. It is mainly caused by the m.8344A > G mutation in the tRNALys (UUR) gene of mtDNA (MT-TK gene). This mutation affects the translation of mtDNA encoded proteins; therefore, the assembly of the electron transport chain (ETC) complexes is disrupted, leading to a reduced mitochondrial respiratory function. However, the molecular pathogenesis of MERRF syndrome remains poorly understood due to the lack of appropriate cell models, particularly in those cell types most affected in the disease such as neurons. Patient-specific induced neurons (iNs) are originated from dermal fibroblasts derived from different individuals carrying the particular mutation causing the disease. Therefore, patient-specific iNs can be used as an excellent cell model to elucidate the mechanisms underlying MERRF syndrome. Here we present for the first time the generation of iNs from MERRF dermal fibroblasts by direct reprograming, as well as a series of pathophysiological characterizations which can be used for testing the impact of a specific mtDNA mutation on neurons and screening for drugs that can correct the phenotype.

Keywords: Direct reprogramming; Induced neurons; MERRF; Mitochondria; Mitochondrial diseases

DOI: https://doi.org/10.1016/j.bbamcr.2019.02.010

Nature. 2019 Feb 27.

Author Correction: Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations.

Change history In this Letter, there are several errors regarding the assignments of mtDNA haplotypes for a subset of egg donors from our study. These errors have not been corrected online.

DOI: https://doi.org/10.1038/s41586-019-0876-1

Annu Rev Plant Biol. 2019 Mar 01.

Assembly of the Complexes of the Oxidative Phosphorylation System in Land Plant Mitochondria.

Etienne H Meyer, Elina Welchen, Chris Carrie.

Plant mitochondria play a major role during respiration by producing the ATP required for metabolism and growth. ATP is produced during oxidative phosphorylation (OXPHOS), a metabolic pathway coupling electron transfer with ADP phosphorylation via the formation and release of a proton gradient across the inner mitochondrial membrane. The OXPHOS system is composed of large, multiprotein complexes coordinating metal-containing cofactors for the transfer of electrons. In this review, we summarize the current state of knowledge about assembly of the OXPHOS complexes in land plants. We present the different steps involved in the formation of functional complexes and the regulatory mechanisms controlling the assembly pathways. Because several assembly steps have been found to be ancestral in plants-compared with those described in fungal and animal models-we discuss the evolutionary dynamics that lead to the conservation of ancestral pathways in land plant mitochondria. Expected final online publication date for the Annual Review of Plant Biology Volume 70 is April 29, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-arplant-050718-100412