Abstract
To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.
Highlights
Without a sufficient regenerative capacity, a nervous system’s form and function critically depends on the molecular and cellular mechanisms that support its cells’ longevity
We used a transgenic line in which an inducible heat shock promoter drives ubiquitous expression of a dominant negative IGF1Ra [Tg] (Kamei et al, 2011). dnIGF1Ra-GFP expression was induced from 24 hr post fertilization to 5 days post fertilization
Consistent with these results, we found that post-developmental attenuation of IGF1 receptors (IGF1Rs) signaling, through induction of dnIGF1Ra-GFP expression beginning at four dpf, was sufficient to reduce hair cell survival when exposed to neomycin at five dpf (Figure 4C)
Summary
Without a sufficient regenerative capacity, a nervous system’s form and function critically depends on the molecular and cellular mechanisms that support its cells’ longevity. Metabolic energy is primarily supplied by mitochondrial oxidative phosphorylation (Kann and Kovacs, 2007) This process is essential to cell survival, a cytotoxic consequence is the generation of reactive oxygen species (ROS). Neural cells are vulnerable to oxidative stress due to their energy demand and thereby ROS production, and to their relatively insufficient antioxidant capacity (Halliwell, 1992). This heightened susceptibility to oxidative stress-mediated cell death is believed to underlie aging and neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS) (Perry et al, 2002; Barber et al, 2006; Mattson and Magnus, 2006; Blesa et al, 2015)
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