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Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism

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Abstract

Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain. Megalin mutations underlie the pathogenesis of Donnai–Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-β to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.

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Abbreviations

STC1:

Stanniocalcin-1

KO:

Knockout

AMPK:

AMP-activated kinase

megalin/Lrp2:

Low-density lipoprotein-related protein-2

UCP:

Uncoupling protein

Sirt3:

Sirtuin 3

PT:

Proximal tubule

TKPTS:

Mouse proximal tubule cells

HEK293T:

Human embryonic kidney

Raw264.7:

Murine macrophage-like

C2C12:

Murine muscle

CRISPR:

Clustered regularly-interspaced short palindromic repeats

Cas9:

CRISPR-associated protein 9

Golgi 97:

Golgi-associated protein 97

FLAG:

DYKDDDDK epitope tag

Mito-Red:

Red-fluorescent dye

RAB7:

Rab GTPase 7 regulates late endocytic trafficking downstream of multivesicular body

CID1067700:

An inhibitor of Rab7

E-64D:

Lysosome inhibitor

ROS:

Reactive oxygen species

OCRL1:

Inositol polyphosphate 5-phosphatase

NAD:

Nicotinamide adenine dinucleotide

PIKfyve:

Fyve-type zinc finger-containing phosphoinositide kinase

YM201636:

PIKfyve inhibitor

PtdIns3P:

Phosphatidylinositol 3-phosphate

OCR:

Oxygen consumption rate

ECAR:

Extracellular acidification rate

LHRH:

Luteinizing hormone-releasing hormone

TRH:

Thyrotropin-releasing hormone

IGF-1:

Insulin-like growth factor-1

IL-33:

Interleukin-33

INF-α and -γ:

Interferon-α and -γ

PLA2-I:

Phospholipase A2

VIP:

Vasoactive intestinal peptide

ANP:

Atrial natriuretic peptide

Wnt 13:

Wingless/integrated 13

AT1:

Angiotensin II type 1

GLUT4:

Glucose transporter 4

Atg9:

Autophagy-related protein 9

EGFR:

Epidermal growth factor receptor

FCCP:

Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone

HSP60:

Heat shock protein 60

Vdac1:

Voltage-dependent anion-selective channel 1

VPS:

Vacuolar protein sorting

IHC:

Immunohistochemistry

Mia40/Erv1:

Disulfide relay system that drives the import of cysteine-rich proteins into the inter-mitochondrial space

Mitoblock-6:

An inhibitor of Mia40/Erv1

TOM40:

Subunit of the mitochondrial outer membrane translocase

Rab32:

Ras-related protein, anchors the regulatory subunit of protein kinase A to the mitochondria

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Acknowledgements

This work was supported by Grants from: The Veteran Administration (BX002006 and IK2 BX002912); National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (R01 DK080306); USDA CRIS 3092-5-001-059, and a generous gift from Dr. and Mrs. Harold Selzman. This project was also supported by the Pathology and Histology Core at Baylor College of Medicine, with funding from the NIH (NCI P30-CA125123), and the expert assistance of Michael Ittmann, M.D., Ph.D. We thank Dr. Stuart Dryer for critical reading of the manuscript. Imaging for this project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338, and CA125123), CPRIT (RP150578), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

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Author notes

  1. Co-first authors: Qingtian Li and Fan Lei.

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine, One Baylor Plaza, ABBR R706, M/S BCM395, Houston, TX, 77030-3498, USA

    Qingtian Li, Fan Lei, Yi Tang, Jenny Szu-Chin Pan & David Sheikh-Hamad

  2. Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China

    Fan Lei

  3. West China Medical Center of Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Yi Tang

  4. Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Qiang Tong

  5. Department of Nutrition and Food Science (NFSC), Texas A&M University, College Station, TX, 77843, USA

    Yuxiang Sun

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  1. Qingtian Li
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  2. Fan Lei
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Contributions

QL: design, cloning, carried out experiments, prepared figures and edited manuscript; LF: carried out experiments; YT: carried out experiments; JSCP: carried out experiments and edited manuscript; QT: generation of SIRT3 plasmids; YS: design and edited manuscript; DSH: conception, design, manuscript writing and figures preparation, communication.

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Correspondence to David Sheikh-Hamad.

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Li, Q., Lei, F., Tang, Y. et al. Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism. Cell. Mol. Life Sci. 75, 4021–4040 (2018). https://doi.org/10.1007/s00018-018-2847-3

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