2. Academic Validation
  3. Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors

Mitochondrial permeability transition dictates mitochondrial maturation upon switch in cellular identity of hematopoietic precursors

  • Commun Biol. 2024 Aug 9;7(1):967. doi: 10.1038/s42003-024-06671-y.
Sandeep P Dumbali # 1,  Paulina D Horton # 1 2 3,  Travis I Moore 1 4,  Pamela L Wenzel 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 2 Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 3 Immunology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 4 Molecular & Translational Biology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 5 Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. pamela.l.wenzel@uth.tmc.edu.
  • 6 Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. pamela.l.wenzel@uth.tmc.edu.
  • 7 Immunology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. pamela.l.wenzel@uth.tmc.edu.
  • 8 Molecular & Translational Biology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. pamela.l.wenzel@uth.tmc.edu.
  • # Contributed equally.
PMID: 39122870 DOI: 10.1038/s42003-024-06671-y
Abstract

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular identity, mPTP conductance is restored. In utero treatment with NIM811, a molecule that blocks sensitization of the mPTP to opening by Cyclophilin D (CypD), amplifies Oxidative Phosphorylation (OXPHOS) in hematopoietic precursors and increases hematopoiesis in the embryo. Additionally, differentiating pluripotent stem cells (PSCs) acquire greater organization of mitochondrial cristae and hematopoietic activity following knockdown of the CypD gene, Ppif. Conversely, knockdown of Opa1, a GTPase critical for proper cristae architecture, induces cristae irregularity and impairs hematopoiesis. These data elucidate a mechanism that regulates mitochondrial maturation in hematopoietic precursors and underscore a role for the mPTP in the acquisition of hematopoietic fate.

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