bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–05–25
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. De novo serine biosynthesis is protective in mitochondrial disease.
  2. Silencing mitochondrial gene expression in living cells.
  1. Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710
    De novo serine biosynthesis is protective in mitochondrial disease.
    Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.
      The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.
    Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115710
  2. Science. 2025 May 22. eadr3498
    Silencing mitochondrial gene expression in living cells.
    Luis Daniel Cruz-Zaragoza, Drishan Dahal, Mats Koschel, Angela Boshnakovska, Aiturgan Zheenbekova, Mehmet Yilmaz, Marcel Morgenstern, Jan-Niklas Dohrke, Julian Bender, Anusha Valpadashi, Kristine A Henningfeld, Silke Oeljeklaus, Laura Sophie Kremer, Mirjam Breuer, Oliver Urbach, Sven Dennerlein, Michael Lidschreiber, Stefan Jakobs, Bettina Warscheid, Peter Rehling.
      Mitochondria fulfill central functions in metabolism and energy supply. They express their own genome, which encodes key subunits of the oxidative phosphorylation system. However, central mechanisms underlying mitochondrial gene expression remain enigmatic. A lack of suitable technologies to target mitochondrial protein synthesis in cells has limited experimental access. Here, we silenced the translation of specific mitochondrial mRNAs in living human cells by delivering synthetic peptide-morpholino chimeras. This approach allowed us to perform a comprehensive temporal monitoring of cellular responses. Our study provides insights into mitochondrial translation, its integration into cellular physiology, and provides a strategy to address mitochondrial gene expression in living cells. The approach can potentially be used to analyze mechanisms and pathophysiology of mitochondrial gene expression in a range of cellular model systems.
    DOI:  https://doi.org/10.1126/science.adr3498
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