bims-iorami 2023-10-15 papers

Issue of 2023–10–15
six papers selected by
Chenxiao Yu, Soochow University

Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]

Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.

Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.

Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.

Keywords: ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import

DOI: https://doi.org/10.1016/j.molcel.2023.09.026

Cell Death Differ. 2023 Oct 12.

Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids.

Pengfei Yang, Jin Li, Tianyi Zhang, Yanxian Ren, Qiuning Zhang, Ruifeng Liu, Haining Li, Junrui Hua, Wen-An Wang, Jufang Wang, Heng Zhou.

Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.

DOI: https://doi.org/10.1038/s41418-023-01230-0

J Biomed Sci. 2023 Oct 12. 30(1): 86

Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.

Lei Liu, Yanjun Li, Guo Chen, Quan Chen.

Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.

Keywords: Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors

DOI: https://doi.org/10.1186/s12929-023-00975-7

Nature. 2023 Oct 11.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

DOI: https://doi.org/10.1038/s41586-023-06621-4

Int J Mol Sci. 2023 Oct 03. pii: 14858. [Epub ahead of print]24(19):

N6-Methyladenine Progressively Accumulates in Mitochondrial DNA during Aging.

Ádám Sturm, Himani Sharma, Ferenc Bodnár, Maryam Aslam, Tibor Kovács, Ákos Németh, Bernadette Hotzi, Viktor Billes, Tímea Sigmond, Kitti Tátrai, Balázs Egyed, Blanka Téglás-Huszár, Gitta Schlosser, Nikolaos Charmpilas, Christina Ploumi, András Perczel, Nektarios Tavernarakis, Tibor Vellai.

N6-methyladenine (6mA) in the DNA is a conserved epigenetic mark with various cellular, physiological and developmental functions. Although the presence of 6mA was discovered a few years ago in the nuclear genome of distantly related animal taxa and just recently in mammalian mitochondrial DNA (mtDNA), accumulating evidence at present seriously questions the presence of N6-adenine methylation in these genetic systems, attributing it to methodological errors. In this paper, we present a reliable, PCR-based method to determine accurately the relative 6mA levels in the mtDNA of Caenorhabditis elegans, Drosophila melanogaster and dogs, and show that these levels gradually increase with age. Furthermore, daf-2(-)-mutant worms, which are defective for insulin/IGF-1 (insulin-like growth factor) signaling and live twice as long as the wild type, display a half rate at which 6mA progressively accumulates in the mtDNA as compared to normal values. Together, these results suggest a fundamental role for mtDNA N6-adenine methylation in aging and reveal an efficient diagnostic technique to determine age using DNA.

Keywords: C. elegans; Drosophila; N6-adenine methylation; N6-methyladenine levels; age determination; aging; dog; mitochondrial genome

DOI: https://doi.org/10.3390/ijms241914858

FASEB Bioadv. 2023 Oct;5(10): 412-426

Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple-negative breast cancer patients for potential biomarker development.

Kunwar Somesh Vikramdeo, Shashi Anand, Sarabjeet Kour Sudan, Paramahansa Pramanik, Seema Singh, Andrew K Godwin, Ajay Pratap Singh, Santanu Dasgupta.

Early detection and recurrence prediction are challenging in triple-negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)-based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next-generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%-38% TNBCs, which were detectable in the serum-derived EVs with 82% specificity. Overall, 38% of the metastatic tumor-signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI-specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor-signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.

Keywords: extracellular vesicles; liquid biomarker; mitochondrial DNA; mutation; triple‐negative breast cancer

DOI: https://doi.org/10.1096/fba.2023-00070