Cellular and Molecular Life Sciences

, Volume 75, Issue 21, pp 4021–4040 | Cite as

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

  • Qingtian Li
  • Fan Lei
  • Yi Tang
  • Jenny Szu-Chin Pan
  • Qiang Tong
  • Yuxiang Sun
  • David Sheikh-HamadEmail author
Original Article


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.


Proteinuria ApoE Vitamin D OCRL1 PIKfyve Sonic hedgehog 







AMP-activated kinase


Low-density lipoprotein-related protein-2


Uncoupling protein


Sirtuin 3


Proximal tubule


Mouse proximal tubule cells


Human embryonic kidney


Murine macrophage-like


Murine muscle


Clustered regularly-interspaced short palindromic repeats


CRISPR-associated protein 9

Golgi 97

Golgi-associated protein 97


DYKDDDDK epitope tag


Red-fluorescent dye


Rab GTPase 7 regulates late endocytic trafficking downstream of multivesicular body


An inhibitor of Rab7


Lysosome inhibitor


Reactive oxygen species


Inositol polyphosphate 5-phosphatase


Nicotinamide adenine dinucleotide


Fyve-type zinc finger-containing phosphoinositide kinase


PIKfyve inhibitor


Phosphatidylinositol 3-phosphate


Oxygen consumption rate


Extracellular acidification rate


Luteinizing hormone-releasing hormone


Thyrotropin-releasing hormone


Insulin-like growth factor-1



INF-α and -γ

Interferon-α and -γ


Phospholipase A2


Vasoactive intestinal peptide


Atrial natriuretic peptide

Wnt 13

Wingless/integrated 13


Angiotensin II type 1


Glucose transporter 4


Autophagy-related protein 9


Epidermal growth factor receptor


Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone


Heat shock protein 60


Voltage-dependent anion-selective channel 1


Vacuolar protein sorting




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


An inhibitor of Mia40/Erv1


Subunit of the mitochondrial outer membrane translocase


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



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.

Author 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.

Compliance with ethical standards

Conflict of interest

No financial interests to disclose.

Supplementary material

18_2018_2847_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1903 kb)


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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Division of Nephrology, Department of Medicine, Selzman Institute for Kidney HealthBaylor College of MedicineHoustonUSA
  2. 2.Renmin Hospital of Wuhan UniversityWuhanPeople’s Republic of China
  3. 3.West China Medical Center of Sichuan UniversityChengduPeople’s Republic of China
  4. 4.Children’s Nutrition Research CenterBaylor College of MedicineHoustonUSA
  5. 5.Department of Nutrition and Food Science (NFSC)Texas A&M UniversityCollege StationUSA

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