transforming-growth-factor-beta and Hearing-Loss--Sensorineural

Loss of auditory neurons is commonly associated with sensorineural deafness, and may result from either direct neuronal injury or be a consequence of sensory hair cell loss (i.e. loss of source of trophic factors). Developmental studies and in vitro studies of adult neurons have begun to identify growth factors important for the development, maintenance, and rescue/repair of auditory neurons. Specific neurotrophic factors have been shown to enhance the auditory neurons' ability to withstand traumatic loss of target tissue connections and toxic injury. Promising initial in vivo studies confirm that specific neurotrophins are able to support neuronal survival and promote neuronal repair in an intact animal following injury to the cochlea. Further study into unique methods and routes of growth factor delivery will provide insights into the possibility of neurotrophic growth factors to act as drugs for the treatment of injured or stressed auditory neurons.

Topics: Animals; Cells, Cultured; Cochlea; Fibroblast Growth Factor 2; Hearing Loss, Sensorineural; In Vitro Techniques; Rats; Spiral Ganglion; Transforming Growth Factor beta; Vestibulocochlear Nerve

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.

Topics: Agenesis of Corpus Callosum; Amyloid beta-Peptides; Animals; Brain; Cell Membrane; Glycoproteins; Hearing Loss, Sensorineural; HEK293 Cells; Hernias, Diaphragmatic, Congenital; Humans; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Mitochondria; Myopia; Oculocerebrorenal Syndrome; Proteinuria; rab GTP-Binding Proteins; RAW 264.7 Cells; Renal Tubular Transport, Inborn Errors; Signal Transduction; Sirtuin 3; Transforming Growth Factor beta