bims-minimp 2022-04-24 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒04‒24
eleven papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.
Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis.
Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease.
Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.
Organization and expression of the mammalian mitochondrial genome.
A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
GET pathway mediates transfer of mislocalized tail-anchored proteins from mitochondria to the ER.
Phospholipids alter activity and stability of mitochondrial membrane-bound ubiquitin ligase MARCH5.
Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.

Dev Cell. 2022 Apr 14. pii: S1534-5807(22)00229-5. [Epub ahead of print]

Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.

Kai Cao, Joel S Riley, Rosalie Heilig, Alfredo E Montes-Gómez, Esmee Vringer, Kevin Berthenet, Catherine Cloix, Yassmin Elmasry, David G Spiller, Gabriel Ichim, Kirsteen J Campbell, Andrew P Gilmore, Stephen W G Tait.

  Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.

Keywords:  DNA damage; MOMP; apoptosis; cancer; caspase; cell death; fission; fusion; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.devcel.2022.03.019
Mol Biol Cell. 2022 Apr 21. mbcE21110553

Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis.

Lukasz Samluk, Piotr Ostapczuk, Magdalena Dziembowska.

Accumulating evidence indicates that mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases. Both of these conditions are often associated with an increase in protein aggregation. However, still unknown are the specific defects of mitochondrial biology that play a critical role in the development of Alzheimer's disease, in which Tau protein aggregates are observed in some patients' brains. Here, we report that long-term mitochondrial stress triggered Tau dimerization, which is the first step of protein aggregation. Mitochondrial dysfunction was induced in HEK293T cells that received prolonged treatment with rotenone and in HEK293T cells with the knockout of NDUFA11 protein. To monitor changes in Tau protein aggregation, we took advantage of the bimolecular fluorescence complementation assay using HEK293T cells that were transfected with plasmids that encoded Tau. Inhibition of the ISR with ISRIB induced Tau dimerization, whereas ISR activation with salubrinal, guanabenz, and sephin1 partially reversed this process. Cells that were treated with ROS scavengers, N-acetyl-L-cysteine or MitoQ, significantly reduced the amount of ROS and Tau dimerization, indicating the involvement of oxidative stress in Tau aggregation. Our results indicate that long-term mitochondrial stress may induce early steps of Tau protein aggregation by affecting oxidative balance and cellular proteostasis.

DOI: https://doi.org/10.1091/mbc.E21-11-0553
Cells. 2022 Apr 16. pii: 1363. [Epub ahead of print]11(8):

Organismal and Cellular Stress Responses upon Disruption of Mitochondrial Lonp1 Protease.

Eirini Taouktsi, Eleni Kyriakou, Stefanos Smyrniotis, Fivos Borbolis, Labrina Bondi, Socratis Avgeris, Efstathios Trigazis, Stamatis Rigas, Gerassimos E Voutsinas, Popi Syntichaki.

  Cells engage complex surveillance mechanisms to maintain mitochondrial function and protein homeostasis. LonP1 protease is a key component of mitochondrial quality control and has been implicated in human malignancies and other pathological disorders. Here, we employed two experimental systems, the worm Caenorhabditis elegans and human cancer cells, to investigate and compare the effects of LONP-1/LonP1 deficiency at the molecular, cellular, and organismal levels. Deletion of the lonp-1 gene in worms disturbed mitochondrial function, provoked reactive oxygen species accumulation, and impaired normal processes, such as growth, behavior, and lifespan. The viability of lonp-1 mutants was dependent on the activity of the ATFS-1 transcription factor, and loss of LONP-1 evoked retrograde signaling that involved both the mitochondrial and cytoplasmic unfolded protein response (UPRmt and UPRcyt) pathways and ensuing diverse organismal stress responses. Exposure of worms to triterpenoid CDDO-Me, an inhibitor of human LonP1, stimulated only UPRcyt responses. In cancer cells, CDDO-Me induced key components of the integrated stress response (ISR), the UPRmt and UPRcyt pathways, and the redox machinery. However, genetic knockdown of LonP1 revealed a genotype-specific cellular response and induced apoptosis similar to CDDO-Me treatment. Overall, the mitochondrial dysfunction ensued by disruption of LonP1 elicits adaptive cytoprotective mechanisms that can inhibit cancer cell survival but diversely modulate organismal stress response and aging.

Keywords:  C. elegans; CDDO-Me; LonP1; aging; cancer; mitochondria

DOI:  https://doi.org/10.3390/cells11081363
Front Cell Dev Biol. 2022 ;10 874596

Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?

Irene H Flønes, Charalampos Tzoulis.

  Parkinson's disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of α -synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.

Keywords:  Parkinson's disease; mitochondria; mitochondrial complex I; neurodegeneration; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fcell.2022.874596
Stem Cell Rev Rep. 2022 Apr 23.

Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.

Xingyu Gao, Xiao Yu, Chang Zhang, Yiming Wang, Yanan Sun, Hui Sun, Haiying Zhang, Yingai Shi, Xu He.

  Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.

Keywords:  Aging; Cellular senescence; Mitochondrial metabolism; Telomeres

DOI:  https://doi.org/10.1007/s12015-022-10370-8
Nat Rev Genet. 2022 Apr 22.

Organization and expression of the mammalian mitochondrial genome.

Oliver Rackham, Aleksandra Filipovska.

The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.

DOI: https://doi.org/10.1038/s41576-022-00480-x
Elife. 2022 Apr 22. pii: e71634. [Epub ahead of print]11

A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.

James P Held, Gaomin Feng, Benjamin R Saunders, Claudia V Pereria, Kristopher Burkewitz, Maulik R Patel.

  The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.

Keywords:  C. elegans; cell biology

DOI:  https://doi.org/10.7554/eLife.71634
J Cell Biol. 2022 Jun 06. pii: e202104076. [Epub ahead of print]221(6):

GET pathway mediates transfer of mislocalized tail-anchored proteins from mitochondria to the ER.

Shunsuke Matsumoto, Suzuka Ono, Saori Shinoda, Chika Kakuta, Satoshi Okada, Takashi Ito, Tomoyuki Numata, Toshiya Endo.

Tail-anchored (TA) membrane proteins have a potential risk to be mistargeted to the mitochondrial outer membrane (OM). Such mislocalized TA proteins can be extracted by the mitochondrial AAA-ATPase Msp1 from the OM and transferred to the ER for ER protein quality control involving ubiquitination by the ER-resident Doa10 complex. Yet it remains unclear how the extracted TA proteins can move to the ER crossing the aqueous cytosol and whether this transfer to the ER is essential for the clearance of mislocalized TA proteins. Here we show by time-lapse microscopy that mislocalized TA proteins, including an authentic ER-TA protein, indeed move from mitochondria to the ER in a manner strictly dependent on Msp1 expression. The Msp1-dependent mitochondria-to-ER transfer of TA proteins is blocked by defects in the GET system, and this block is not due to impaired Doa10 functions. Thus, the GET pathway facilitates the transfer of mislocalized TA proteins from mitochondria to the ER.

DOI: https://doi.org/10.1083/jcb.202104076
Life Sci Alliance. 2022 Aug;pii: e202101309. [Epub ahead of print]5(8):

Phospholipids alter activity and stability of mitochondrial membrane-bound ubiquitin ligase MARCH5.

Lisa Merklinger, Johannes Bauer, Per A Pedersen, Rune Busk Damgaard, J Preben Morth.

Mitochondrial homeostasis is tightly controlled by ubiquitination. The mitochondrial integral membrane ubiquitin ligase MARCH5 is a crucial regulator of mitochondrial membrane fission, fusion, and disposal through mitophagy. In addition, the lipid composition of mitochondrial membranes can determine mitochondrial dynamics and organelle turnover. However, how lipids influence the ubiquitination processes that control mitochondrial homeostasis remains unknown. Here, we show that lipids common to the mitochondrial membranes interact with MARCH5 and affect its activity and stability depending on the lipid composition in vitro. As the only one of the tested lipids, cardiolipin binding to purified MARCH5 induces a significant decrease in thermal stability, whereas stabilisation increases the strongest in the presence of phosphatidic acid. Furthermore, we observe that the addition of lipids to purified MARCH5 alters the ubiquitination pattern. Specifically, cardiolipin enhances auto-ubiquitination of MARCH5. Our work shows that lipids can directly affect the activity of ubiquitin ligases and suggests that the lipid composition in mitochondrial membranes could control ubiquitination-dependent mechanisms that regulate the dynamics and turnover of mitochondria.

DOI: https://doi.org/10.26508/lsa.202101309
Semin Cell Dev Biol. 2022 Apr 18. pii: S1084-9521(22)00122-7. [Epub ahead of print]

Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.

Helin Hocaoglu, Matthew Sieber.

  Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration. Mitochondrial metabolism dynamically changes as tissues transition through distinct phases of development. These organelles support the energetic and biosynthetic demands of developing cells and function as key structures that coordinate the nutrient status of the organism with developmental progression. This review will examine the mechanisms that link mitochondria to developmental processes. We will also examine the process of mitochondrial respiratory quiescence (MRQ), a novel mechanism for regulating cellular metabolism through the biochemical and physiological remodeling of mitochondria. Lastly, we will examine MRQ as a system to discover the mechanisms that drive mitochondrial remodeling during development.

Keywords:  Cancer; Drosophila; Metabolism; Mitochondria; Oocytes; Quiescence; Reprogramming; Stem cells

DOI:  https://doi.org/10.1016/j.semcdb.2022.03.040
Int J Mol Sci. 2022 Apr 08. pii: 4149. [Epub ahead of print]23(8):

Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency.

Liza Douiev, Chaya Miller, Guy Keller, Hadar Benyamini, Bassam Abu-Libdeh, Ann Saada.

  Cytochrome c oxidase (COX), a multimeric protein complex, is the final electron acceptor in the mitochondrial electron transfer chain. Primary COX deficiency, caused by mutations in either mitochondrial DNA or nuclear-encoded genes, is a heterogenous group of mitochondrial diseases with a wide range of presentations, ranging from fatal infantile to subtler. We previously reported a patient with primary COX deficiency due to a pathogenic variant in COX4I1 (encoding the common isoform of COX subunit 4, COX4-1), who presented with bone marrow failure, genomic instability, and short stature, mimicking Fanconi anemia (FA). In the present study, we demonstrated that accumulative DNA damage coincided primarily with proliferative cells in the patient's fibroblasts and in COX4i1 knockdown cells. Expression analysis implicated a reduction in DNA damage response pathways, which was verified by demonstrating impaired recovery from genotoxic insult and decreased DNA repair. The premature senescence of the COX4-1-deficient cells prevented us from undertaking additional studies; nevertheless, taken together, our results indicate replicative stress and impaired nuclear DNA damage response in COX4-1 deficiency. Interestingly, our in vitro findings recapitulated the patient's presentation and present status.

Keywords:  COX4i1; DNA damage; cytochrome c oxidase; mitochondria; mitochondrial respiratory chain; replicative stress

DOI:  https://doi.org/10.3390/ijms23084149