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Metabolic Syndrome Modulates Protein Import into the Mitochondria of Porcine Mesenchymal Stem Cells

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Abstract

Mesenchymal stem cells (MSCs) are currently being tested in several clinical trials. Mitochondria regulate many aspects of MSC function. Mitochondrial preproteins are rapidly translated and trafficked into the mitochondrion for assembly in their final destination, but whether coexisting cardiovascular risk factors modulate this process is unknown. We hypothesized that metabolic syndrome (MetS) modulates mitochondrial protein import in porcine MSCs. MSCs were isolated from porcine abdominal adipose tissue after 16 weeks of Lean or MetS diet (n = 5 each). RNA-sequencing was performed and differentially expressed mitochondrial mRNAs and microRNAs were identified and validated. Protein expression of transporters of mitochondrial proteins (presequences and precursors) and their respective substrates were measured. Mitochondrial homeostasis was assessed by Western blot and function by cytochrome-c oxidase-IV activity. Forty-five mitochondrial mRNAs were upregulated and 25 downregulated in MetS-MSCs compared to Lean-MSCs. mRNAs upregulated in MetS-MSCs encoded for precursor proteins, whereas those downregulated encoded for presequences. Micro-RNAs upregulated in MetS-MSCs primarily target mRNAs encoding for presequences. Transporters of precursor proteins and their substrates were also upregulated, associated with changes in mitochondrial homeostasis and dysfunction. MetS interferes with mitochondrial protein import, favoring upregulation of precursor proteins, which might be linked to post-transcriptional regulation of presequences. This in turn alters mitochondrial homeostasis and impairs energy production. Our observations highlight the importance of mitochondria in MSC function and provide a molecular framework for optimization of cell-based strategies as we move towards their clinical application.

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Acknowledgements

This study was partly supported by the NIH grant numbers: DK104273, HL123160, and DK102325, DK106427, and the Mayo Clinic: Mary Kathryn and Michael B. Panitch Career Development Award. The funding sources had no involvement in study design, conduct, analysis or interpretation of the results.

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Authors and Affiliations

  1. Divisions of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Arash Aghajani Nargesi, Xiang-Yang Zhu, LaTonya J. Hickson, Sabena M. Conley, Lilach O. Lerman & Alfonso Eirin

  2. Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA

    Andre J. van Wijnen

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  1. Arash Aghajani Nargesi
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  2. Xiang-Yang Zhu
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  3. LaTonya J. Hickson
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  4. Sabena M. Conley
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  5. Andre J. van Wijnen
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  6. Lilach O. Lerman
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  7. Alfonso Eirin
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Correspondence to Alfonso Eirin.

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The authors do not have any financial conflict of interests to disclose.

Research Involving Animals

All experiments were conducted with the approval of the Mayo Clinic Animal Care and Use Committee (approval case number: A00003694–18), which regulates and establishes procedures for the scientific use of animals.

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Aghajani Nargesi, A., Zhu, XY., Hickson, L.J. et al. Metabolic Syndrome Modulates Protein Import into the Mitochondria of Porcine Mesenchymal Stem Cells. Stem Cell Rev and Rep 15, 427–438 (2019). https://doi.org/10.1007/s12015-018-9855-4

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  • DOI: https://doi.org/10.1007/s12015-018-9855-4

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