bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2025–01–19
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. In depth profiling of dihydrolipoamide dehydrogenase deficiency in primary patients fibroblasts reveals metabolic reprogramming secondary to mitochondrial dysfunction.
  2. Interaction and regulation of the mitochondrial proteome - in health and disease.
  1. Mol Genet Metab Rep. 2025 Mar;42 101172
    In depth profiling of dihydrolipoamide dehydrogenase deficiency in primary patients fibroblasts reveals metabolic reprogramming secondary to mitochondrial dysfunction.
    Uri Sprecher, Jeevitha Dsouza, Monzer Marisat, Dinorah Barasch, Kumudesh Mishra, Or Kakhlon, Joshua Manor, Yair Anikster, Miguel Weil.
      Dihydrolipoamide dehydrogenase (DLD) deficiency is an autosomal recessive disorder characterized by a functional disruption in several critical mitochondrial enzyme complexes, including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Despite DLD's pivotal role in cellular energy metabolism, detailed molecular and metabolic consequences of DLD deficiency (DLDD) remain poorly understood. This study represents the first in-depth multi-omics analysis, specifically metabolomic and transcriptomic, of fibroblasts derived from a DLD-deficient patient compound heterozygous for a common Ashkenazi Jewish variant (c.685G > T) and a novel North African variant (c.158G > A). The investigation reveals significant metabolic disruptions that distinguish the cellular phenotype of DLDD from other metabolic disorders and healthy controls. Employing a range of cellular and molecular techniques, including live-cell imaging, mitochondrial activity assays, immunofluorescence, transcriptomics and metabolomic analysis, we compared DLDD fibroblasts with fibroblasts from glycogen storage disease type 1 A (GSD1a) patients and healthy controls (HC) subjects. Our metabolomics analysis identified significant alterations in mitochondrial metabolism, particularly reduced glycine cleavage, altered one carbon metabolism and serine catabolism. Transcriptome profiling highlighted dysregulation in genes associated with metabolic stress and mitochondrial dysfunction. Our findings highlight reduced mitochondrial activity and respiratory capacity in DLDD fibroblasts, similar to observations in GSD1a fibroblasts. This multi-omics approach not only advances our understanding of the pathophysiology of DLDD, but also illustrates the potential for developing targeted diagnostics and therapeutic strategies.
    Keywords:  Dihydrolipoamide dehydrogenase deficiency; Image based high content analysis; Metabolic disorder; Metabolomics; Mitochondrial activity; Next generation sequencing; Patient study; Primary skin fibroblasts; RNA -seq
    DOI:  https://doi.org/10.1016/j.ymgmr.2024.101172
  2. Expert Rev Proteomics. 2025 Jan 15. 1-15
    Interaction and regulation of the mitochondrial proteome - in health and disease.
    Johan Palmfeldt.
       INTRODUCTION: Mitochondria contain multiple pathways including energy metabolism and several signaling and synthetic pathways. Mitochondrial proteomics is highly valuable for studying diseases including inherited metabolic disorders, complex and common disorders like neurodegeneration, diabetes, and cancer, since they all to some degree have mitochondrial underpinnings.
    AREAS COVERED: The main mitochondrial functions and pathways are outlined, and systematic protein lists are presented. The main energy metabolic pathways are as follows: iron-sulfur cluster synthesis, one carbon metabolism, catabolism of hydrogen sulfide, kynurenines and reactive oxygen species (ROS), and others, described with the aim of laying a foundation for systematic mitochondrial pathway analysis based on proteomics data. The links of the proteins and pathways to functional effects and diseases are discussed. The disease examples are focussed on inherited metabolic disorders, cancer, neurological, and cardiovascular disorders.
    EXPERT OPINION: To elucidate the role of mitochondria in health and disease, there is a need for comprehensive proteomics analyses with stringent, systematic data treatment for proper interpretation of mitochondrial pathway data. In that way, comprehensive hypothesis-based research can be performed based on proteomics data.
    Keywords:  Mitochondrion; NAD; biomarker panels; kynurenine; metabolic disorders; oxidative phosphorylation; proteomics; stress response
    DOI:  https://doi.org/10.1080/14789450.2025.2451704
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒19 at 17:31.