bims-nenemi 2023-04-23 papers

Issue of 2023‒04‒23
seven papers selected by
Marco Tigano
Thomas Jefferson University

Elife. 2023 Apr 19. pii: e87194. [Epub ahead of print]12

Are some mutations more equal than others?

Auden Cote-L'Heureux, Yogesh N K Maithania, Melissa Franco, Konstantin Khrapko.

A large-scale study of mutations in mitochondrial DNA has revealed a subset that do not accumulate with age.

Keywords: aging; duplex sequencing; genetics; genomics; mitochondrial DNA; mouse; somatic mutations

DOI: https://doi.org/10.7554/eLife.87194

Science. 2023 Apr 21. 380(6642): eabj5559

Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1.

Nazma Malik, Bibiana I Ferreira, Pablo E Hollstein, Stephanie D Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S Shadel, Uri Manor, Reuben J Shaw.

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1-dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis.

DOI: https://doi.org/10.1126/science.abj5559

Mol Cells. 2023 Apr 20.

Suboptimal Mitochondrial Activity Facilitates Nuclear Heat Shock Responses for Proteostasis and Genome Stability.

Dongkeun Park, Youngim Yu, Ji-Hyung Kim, Jongbin Lee, Jongmin Park, Kido Hong, Jeong-Kon Seo, Chunghun Lim, Kyung-Tai Min.

Thermal stress induces dynamic changes in nuclear proteins and relevant physiology as a part of the heat shock response (HSR). However, how the nuclear HSR is fine-tuned for cellular homeostasis remains elusive. Here, we show that mitochondrial activity plays an important role in nuclear proteostasis and genome stability through two distinct HSR pathways. Mitochondrial ribosomal protein (MRP) depletion enhanced the nucleolar granule formation of HSP70 and ubiquitin during HSR while facilitating the recovery of damaged nuclear proteins and impaired nucleocytoplasmic transport. Treatment of the mitochondrial proton gradient uncoupler masked MRP-depletion effects, implicating oxidative phosphorylation in these nuclear HSRs. On the other hand, MRP depletion and a reactive oxygen species (ROS) scavenger non-additively decreased mitochondrial ROS generation during HSR, thereby protecting the nuclear genome from DNA damage. These results suggest that suboptimal mitochondrial activity sustains nuclear homeostasis under cellular stress, providing plausible evidence for optimal endosymbiotic evolution via mitochondria-to-nuclear communication.

Keywords: genome stability; heat shock response; mitohormesis; mitonuclear communication; nuclear proteostasis

DOI: https://doi.org/10.14348/molcells.2023.2181

Oncoscience. 2023 ;10 6-8

Mitochondrial regulator ATAD3A: a molecular determinant favoring head and neck cancer development.

Yong Teng.

Keywords: ATAD3A; ERK1/2; anti-cancer target; cancer; mitochondria

DOI: https://doi.org/10.18632/oncoscience.574

bioRxiv. 2023 Apr 07. pii: 2023.04.07.536014. [Epub ahead of print]

Alzheimer's disease-specific cytokine secretion suppresses neuronal mitochondrial metabolism.

Madison K Kuhn, Rebecca M Fleeman, Lynne M Beidler, Amanda M Snyder, Dennis C Chan, Elizabeth A Proctor.

Introduction: Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in Alzheimer's disease patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.Methods: We used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of Alzheimer's disease at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.
Results: We identified a pattern of up-regulated IFNγ, IP-10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.
Conclusions: An Alzheimer's disease-specific pattern of cytokine secretion reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in Alzheimer's disease.

DOI: https://doi.org/10.1101/2023.04.07.536014

Sci Rep. 2023 Apr 20. 13(1): 6445

Watching the human retina breath in real time and the slowing of mitochondrial respiration with age.

Pardis Kaynezhad, Ilias Tachtsidis, Sobha Sivaprasad, Glen Jeffery.

The retina has the greatest metabolic demand in the body particularly in dark adaptation when its sensitivity is enhanced. This requires elevated level of perfusion to sustain mitochondrial activity. However, mitochondrial performance declines with age leading to reduced adaptive ability. We assessed human retina metabolism in vivo using broad band near-infrared spectroscopy (bNIRS), which records colour changes in mitochondria and blood as retinal metabolism shifts in response to changes in environmental luminance. We demonstrate a significant sustained rise in mitochondrial oxidative metabolism in the first 3 min of darkness in subjects under 50 years old. This was not seen in those over 50 years. Choroidal oxygenation declines in < 50 s as mitochondrial metabolism increases, but gradually rises in the > 50 s. Significant group differences in blood oxygenation are apparent in the first 6 min, consistent with mitochondrial demand leading hemodynamic changes. A greater coupling between mitochondrial oxidative metabolism with hemodynamics is revealed in subjects older than 50, possibly due to reduced capacity in the older retina. Rapid in vivo assessment of retinal metabolism with bNIRS provides a route to understanding fundamental physiology and early identification of retinal disease before pathology is established.

DOI: https://doi.org/10.1038/s41598-023-32897-7

Front Pharmacol. 2023 ;14 1136317

Multi-omics analyses reveal ClpP activators disrupt essential mitochondrial pathways in triple-negative breast cancer.

Emily M J Fennell, Lucas J Aponte-Collazo, Wimal Pathmasiri, Blake R Rushing, Natalie K Barker, Megan C Partridge, Yuan-Yuan Li, Cody A White, Yoshimi E Greer, Laura E Herring, Stanley Lipkowitz, Susan C J Sumner, Edwin J Iwanowicz, Lee M Graves.

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

Keywords: CLPP; ClpP activators; breast cancer; mitochondria; multi-omics

DOI: https://doi.org/10.3389/fphar.2023.1136317