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Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure

View ORCID ProfileSvetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Sundar Baral, Xiaonan Liu, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa
doi: https://doi.org/10.1101/2021.01.03.424667
Svetlana Konovalova
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
2Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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  • ORCID record for Svetlana Konovalova
  • For correspondence: svetlana.konovalova@helsinki.fi
Rubén Torregrosa-Muñumer
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Pooja Manjunath
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Sundar Baral
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Xiaonan Liu
2Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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Minna Holopainen
3Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
4Helsinki University Lipidomics Unit HiLIPID, Helsinki Institute of Life Science HiLIFE and Biocenter Finland, Helsinki, Finland
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Jouni Kvist
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Jayasimman Rajendran
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Yang Yang
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Markku Varjosalo
2Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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Reijo Käkelä
3Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
4Helsinki University Lipidomics Unit HiLIPID, Helsinki Institute of Life Science HiLIFE and Biocenter Finland, Helsinki, Finland
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Pentti Somerharju
4Helsinki University Lipidomics Unit HiLIPID, Helsinki Institute of Life Science HiLIFE and Biocenter Finland, Helsinki, Finland
5Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Henna Tyynismaa
1Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
6Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
7Neuroscience Center, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland
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ABSTRACT

Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from GRPEL2 locus on a tightly regulated low level, but induced by heat stress. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. The regulation may occur directly through interaction with PTPMT1, a proximal partner on the CL synthesis pathway, as its product phosphatidylglycerol was also reduced by NERCLIN. We propose that NERCLIN contributes to stress-induced adaptation of mitochondrial dynamics and turnover by regulating the mitochondrial CL content. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.

Competing Interest Statement

The authors have declared no competing interest.

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Posted January 04, 2021.
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Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure
Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Sundar Baral, Xiaonan Liu, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa
bioRxiv 2021.01.03.424667; doi: https://doi.org/10.1101/2021.01.03.424667
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Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure
Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Sundar Baral, Xiaonan Liu, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa
bioRxiv 2021.01.03.424667; doi: https://doi.org/10.1101/2021.01.03.424667

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