bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–04–27
three papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
  2. Origin and evolution of mitochondrial inner membrane composition.
  3. Mechano-metabolism: Recent Findings on the Intersection of Cell Adhesion, Cell Migration, and Metabolism.
  1. Nat Cell Biol. 2025 Apr 21.
    Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism.
    Dohun Kim, Rushendhiran Kesavan, Kevin Ryu, Trishna Dey, Austin Marckx, Cameron Menezes, Prakash P Praharaj, Stewart Morley, Bookyong Ko, Mona H Soflaee, Harrison J Tom, Harrison Brown, Hieu S Vu, Shih-Chia Tso, Chad A Brautigam, Andrew Lemoff, Marcel Mettlen, Prashant Mishra, Feng Cai, Doug K Allen, Gerta Hoxhaj.
      Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.
    DOI:  https://doi.org/10.1038/s41556-025-01655-4
  2. J Cell Sci. 2025 May 01. pii: jcs263780. [Epub ahead of print]138(9):
    Origin and evolution of mitochondrial inner membrane composition.
    Kailash Venkatraman, Nicolas-Frédéric Lipp, Itay Budin.
      Unique membrane architectures and lipid building blocks underlie the metabolic and non-metabolic functions of mitochondria. During eukaryogenesis, mitochondria likely arose from an alphaproteobacterial symbiont of an Asgard archaea-related host cell. Subsequently, mitochondria evolved inner membrane folds known as cristae alongside a specialized lipid composition supported by metabolic and transport machinery. Advancements in phylogenetic methods and genomic and metagenomic data have suggested potential origins for cristae-shaping protein complexes, such as the mitochondrial contact site and cristae-organizing system (MICOS). MICOS protein homologs function in the formation of cristae-like intracytoplasmic membranes (ICMs) in diverse extant alphaproteobacteria. The machinery responsible for synthesizing key mitochondrial phospholipids - which cooperate with cristae-shaping proteins to establish inner membrane architecture - could have also evolved from a bacterial ancestor, but its origins have been less explored. In this Review, we examine the current understanding of mitochondrial membrane evolution, highlighting distinctions between prokaryotic and eukaryotic mitochondrial-specific proteins and lipids and their differing roles in shaping cristae and ICM architecture, and propose a model explaining the concurrent specialization of the mitochondrial lipidome and inner membrane structure in eukaryogenesis. We discuss how advancements across a range of disciplines are shedding light on how multiple membrane components co-evolved to support the central functions of eukaryotic mitochondria.
    Keywords:  Cardiolipin; Cristae; Curvature; Evolution; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.263780
  3. Am J Physiol Cell Physiol. 2025 Apr 24.
    Mechano-metabolism: Recent Findings on the Intersection of Cell Adhesion, Cell Migration, and Metabolism.
    Emily D Fabiano, Jenna M Poole, Cynthia A Reinhart-King.
      Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.
    Keywords:  Extracellular Matrix; Focal Adhesions; Integrins; Metabolism; Migration
    DOI:  https://doi.org/10.1152/ajpcell.00892.2024
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