bims-mitper 2023-01-29 papers

Autophagy. 2023 Jan 24.

Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.

Ayesha Sen, Julia Boix, David Pla-Martín.

Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.

Keywords: - mitophagy; endosomes; mtDNA

DOI: https://doi.org/10.1080/15548627.2023.2170959

Nano Lett. 2023 Jan 23.

Nanoparticle-Based Artificial Mitochondrial DNA Transcription Regulator: MitoScript.

Letao Yang, Christopher Rathnam, Takuya Hidaka, Yannan Hou, Brandon Conklin, Ganesh N Pandian, Hiroshi Sugiyama, Ki-Bum Lee.

The growing knowledge of the links between aberrant mitochondrial gene transcription and human diseases necessitates both an effective and dynamic approach to control mitochondrial DNA (mtDNA) transcription. To address this challenge, we developed a nanoparticle-based synthetic mitochondrial transcription regulator (MitoScript). MitoScript provides great colloidal stability, excellent biocompatibility, efficient cell uptake, and selective mitochondria targeting and can be monitored in live cells using near-infrared fluorescence. Notably, MitoScript controlled mtDNA transcription in a human cell line in an effective and selective manner. MitoScript targeting the light strand promoter region of mtDNA resulted in the downregulation of ND6 gene silencing, which eventually affected cell redox status, with considerably increased reactive oxygen species (ROS) generation. In summary, we developed MitoScript for the efficient, nonviral modification of mitochondrial DNA transcription. Our platform technology can potentially contribute to understanding the fundamental mechanisms of mitochondrial disorders and developing effective treatments for mitochondrial diseases.

Keywords: Artificial transcription factors; Mitochondria DNA (mtDNA) manipulations; Mitochondria-targeted delivery; Nanoclusters; Nanomedicine

DOI: https://doi.org/10.1021/acs.nanolett.2c03958

Crit Rev Clin Lab Sci. 2023 Jan 24. 1-20

Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up.

Abraham J Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch.

The currently available biomarkers generally lack the specificity and sensitivity needed for the diagnosis and follow-up of patients with mitochondrial diseases (MDs). In this group of rare genetic disorders (mutations in approximately 350 genes associated with MDs), all clinical presentations, ages of disease onset and inheritance types are possible. Blood, urine, and cerebrospinal fluid surrogates are well-established biomarkers that are used in clinical practice to assess MD. One of the main challenges is validating specific and sensitive biomarkers for the diagnosis of disease and prediction of disease progression. Profiling of lactate, amino acids, organic acids, and acylcarnitine species is routinely conducted to assess MD patients. New biomarkers, including some proteins and circulating cell-free mitochondrial DNA, with increased diagnostic specificity have been identified in the last decade and have been proposed as potentially useful in the assessment of clinical outcomes. Despite these advances, even these new biomarkers are not sufficiently specific and sensitive to assess MD progression, and new biomarkers that indicate MD progression are urgently needed to monitor the success of novel therapeutic strategies. In this report, we review the mitochondrial biomarkers that are currently analyzed in clinical laboratories, new biomarkers, an overview of the most common laboratory diagnostic techniques, and future directions regarding targeted versus untargeted metabolomic and genomic approaches in the clinical laboratory setting. Brief descriptions of the current methodologies are also provided.

Keywords: Mitochondrial diseases; biomarkers; laboratory diagnosis; mass spectrometry; metabolomics

DOI: https://doi.org/10.1080/10408363.2023.2166013

Structure. 2023 Jan 23. pii: S0969-2126(23)00001-1. [Epub ahead of print]

Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization.

Fiona Aguilar, Stacey Yu, Robert A Grant, Sebastian Swanson, Dia Ghose, Bonnie G Su, Kristopher A Sarosiek, Amy E Keating.

Apoptosis is important for development and tissue homeostasis, and its dysregulation can lead to diseases, including cancer. As an apoptotic effector, BAK undergoes conformational changes that promote mitochondrial outer membrane disruption, leading to cell death. This is termed "activation" and can be induced by peptides from the human proteins BID, BIM, and PUMA. To identify additional peptides that can regulate BAK, we used computational protein design, yeast surface display screening, and structure-based energy scoring to identify 10 diverse new binders. We discovered peptides from the human proteins BNIP5 and PXT1 and three non-native peptides that activate BAK in liposome assays and induce cytochrome c release from mitochondria. Crystal structures and binding studies reveal a high degree of similarity among peptide activators and inhibitors, ruling out a simple function-determining property. Our results shed light on the vast peptide sequence space that can regulate BAK function and will guide the design of BAK-modulating tools and therapeutics.

Keywords: BAK activation; BAK inhibitor; BH3 peptides; BH3 profiling; apoptosis; binding kinetics; peptide design

DOI: https://doi.org/10.1016/j.str.2023.01.001

Eur J Med Chem. 2023 Jan 10. pii: S0223-5234(22)00978-3. [Epub ahead of print]248 115076

Optimization of BAX trigger site activator BTSA1 with improved antitumor potency and in vitro ADMET properties.

Zhenwei Zhang, Shan Zhao, Jiying Pei, Linghui Hou, Shenglin Luan, Hongguang Deng, Dan Liu, Min Huang, Linxiang Zhao.

Direct activation of the pro-apoptotic protein BAX represents a potential therapeutic strategy to trigger apoptosis in cancer. Herein, structural optimization of the reported BAX trigger site activator BTSA1 turned out into a series of pyrazolone derivatives, where compound 6d exhibited significantly enhanced antiproliferative effects and apoptosis induction ability compared to BTSA1. Mechanism of action studies revealed that compound 6d could initiate the BAX activation cascade, promoting BAX insertion into mitochondrial membranes and activating MOMP, ultimately leading to the release of cytochrome c and apoptosis. Furthermore, 6d showed significantly improved in vitro stability and CYPs profile compared to BTSA1. This work may lay a foundation to develop potent BAX trigger site activators for the treatment of BAX-expressing malignancies.

Keywords: Anti-tumor agents; Apoptosis; BAX; Trigger site

DOI: https://doi.org/10.1016/j.ejmech.2022.115076