bims-meprid 2021-10-31 papers

Issue of 2021‒10‒31
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Autophagy. 2021 Oct 27.

Lysosomal targetomics of ghr KO mice shows chaperone-mediated autophagy degrades nucleocytosolic acetyl-coA enzymes.

S Joseph Endicott, Alexander C Monovich, Eric L Huang, Evelynn I Henry, Dennis N Boynton, Logan J Beckmann, Michael J MacCoss, Richard A Miller.

Mice deficient for GHR (growth hormone receptor; ghr KO) have a dramatic lifespan extension, and elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in ghr KO mice downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Following up on these initial proteomics findings, we used a cell culture approach to show that CMA is necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Inhibition of CMA in NIH3T3 cells has been shown to lead to aberrant accumulation of lipid droplets. We show that this lipid droplet phenotype is rescued by knocking down ACLY or ACSS2, suggesting that CMA regulates lipid droplet formation by controlling ACLY and ACSS2. This evidence leads to a model of how constitutive activation of CMA can shape specific metabolic pathways in long-lived endocrine mutant mice.

Keywords: aging; autophagy; growth hormone; metabolism; proteomics

DOI: https://doi.org/10.1080/15548627.2021.1990670

Plant J. 2021 Oct 28.

Acetylation of conserved lysines fine-tunes mitochondrial malate dehydrogenase activity in land plants.

Manuel Balparda, Marlene Elsässer, Mariana B Badia, Jonas Giese, Anastassia Bovdilova, Meike Hüdig, Lisa Reinmuth, Jürgen Eirich, Markus Schwarzländer, Iris Finkemeier, Mareike Schallenberg-Rüdinger, Veronica G Maurino.

Plants need to rapidly and flexibly adjust their metabolism to changes of their immediate environment. Since this necessity results from the sessile lifestyle of land plants, key mechanisms for orchestrating central metabolic acclimation are likely to have evolved early. Here, we explore the role of lysine acetylation as a posttranslational modification to directly modulate metabolic function. We generated a lysine acetylome of the moss Physcomitrium patens and identified 638 lysine acetylation sites, mostly found in mitochondrial and plastidial proteins. A comparison with available angiosperm data pinpointed lysine acetylation as a conserved regulatory strategy in land plants. Focusing on mitochondrial central metabolism, we functionally analyzed acetylation of malate dehydrogenase (mMDH), which acts as a hub of plant metabolic flexibility. In P. patens mMDH1, we detected a single acetylated lysine located next to one of the four acetylation sites detected in Arabidopsis thaliana mMDH1. We assessed the kinetic behavior of recombinant A. thaliana and P. patens mMDH1 with site-specifically incorporated acetyl-lysines. Acetylation of A. thaliana mMDH1 at K169, K170, and K334 decreases its oxaloacetate reduction activity, while acetylation of P. patens mMDH1 at K172 increases this activity. We found modulation of the malate oxidation activity only in A. thaliana mMDH1, where acetylation of K334 highly activated it. Comparative homology modelling of MDH proteins revealed that evolutionarily conserved lysines serve as hotspots of acetylation. Our combined analyses indicate lysine acetylation as a common strategy to fine-tune the activity of central metabolic enzymes with likely impact on plant acclimation capacity.

Keywords: malate dehydrogenase; metabolism; mitochondria; post-transcriptional regulation; protein acetylation

DOI: https://doi.org/10.1111/tpj.15556

Front Oncol. 2021 ;11 676562

Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities.

Jossimar Coronel-Hernández, Eloy Andrés Pérez-Yépez, Izamary Delgado-Waldo, Carlos Contreras-Romero, Nadia Jacobo-Herrera, David Cantú-De León, Carlos Pérez-Plasencia.

Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem.

Keywords: breast cancer; epigenetic modifications; glycolysis; metabolism; therapeutic targets

DOI: https://doi.org/10.3389/fonc.2021.676562