Ca2+ handling and stress responses of photoreceptor mitochondria

Abstract

Maintenance of mitochondrial function and integrity is essential for cellular health. Mitochondria play key roles in ATP generation, cellular signaling, and control of cell death. These functions are linked to mitochondrial Ca2+ content, which until recently has been thought to be controlled primarily by the mitochondrial Ca2+ uniporter (MCU) complex. We characterized this complex in photoreceptors, specialized neurons in the eye that rely on Ca2+ signaling for function, require a high rate of ATP production, and have a unique mitochondrial architecture. I was surprised to find that retinas express exceptionally low levels of MCU protein and that abrogating its expression does not compromise photoreceptor survival or function. Instead, my findings indicate that in the absence of MCU an alternative pathway in photoreceptor mitochondria can support uptake of Ca2+. I also showed that overexpression of MCU in cone photoreceptors accelerates recovery from light stimulation and alters citric acid cycle metabolite pools. MCU overexpression also compromises mitochondrial integrity, but cones can survive this chronic mitochondrial Ca2+ stress for many months. Cones respond to mitochondrial stress (Ca2+, translational, and cold stress) by selectively trafficking damaged mitochondria away from their normal location in the ellipsoid. These mislocalized mitochondria are recycled via lysosomes and can even be exported from the cell. My dissertation highlights the unique characteristics of photoreceptor mitochondria and demonstrates that photoreceptors have adaptations to mitochondrial stress that promote their survival.