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.
Keywords:
ApoE; OCRL1; PIKfyve; Proteinuria; Sonic hedgehog; Vitamin D.
MeSH terms
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Agenesis of Corpus Callosum / genetics
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Agenesis of Corpus Callosum / metabolism
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Agenesis of Corpus Callosum / pathology
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Amyloid beta-Peptides / genetics*
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Amyloid beta-Peptides / metabolism
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Animals
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Brain / metabolism
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Brain / pathology
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Cell Membrane / genetics
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Glycoproteins / genetics
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HEK293 Cells
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Hearing Loss, Sensorineural / genetics
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Hearing Loss, Sensorineural / metabolism
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Hearing Loss, Sensorineural / pathology
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Hernias, Diaphragmatic, Congenital / genetics
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Hernias, Diaphragmatic, Congenital / metabolism
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Hernias, Diaphragmatic, Congenital / pathology
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Humans
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Low Density Lipoprotein Receptor-Related Protein-2 / genetics*
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Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
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Mice
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Mitochondria / genetics*
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Mitochondria / metabolism
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Myopia / genetics
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Myopia / metabolism
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Myopia / pathology
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Oculocerebrorenal Syndrome / genetics
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Oculocerebrorenal Syndrome / metabolism
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Oculocerebrorenal Syndrome / pathology
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Proteinuria / genetics
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Proteinuria / metabolism
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Proteinuria / pathology
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RAW 264.7 Cells
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Renal Tubular Transport, Inborn Errors / genetics
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Renal Tubular Transport, Inborn Errors / metabolism
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Renal Tubular Transport, Inborn Errors / pathology
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Signal Transduction
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Sirtuin 3 / genetics
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Transforming Growth Factor beta / genetics
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rab GTP-Binding Proteins / genetics*
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rab GTP-Binding Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Glycoproteins
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Low Density Lipoprotein Receptor-Related Protein-2
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Transforming Growth Factor beta
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teleocalcin
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SIRT3 protein, human
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Sirtuin 3
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Rab32 protein, human
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rab GTP-Binding Proteins