Suppressors of superoxide production from mitochondrial complex III

Abstract

Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species (ROS), which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies but its role remains controversial. Using high-throughput screening we identified compounds that selectively eliminate superoxide production by complex III without altering oxidative phosphorylation; they modulate retrograde signaling including cellular responses to hypoxic and oxidative stress.

Mitochondrial functions in stem cells

“…As a consequence of electron transfers, superoxide is generated at several mitochondrial sites, which is converted to additional reactive oxygen species that play important roles in retrograde signaling between mitochondrial and other cellular sites [1]. Several metabolites in the tricarboxylic acid cycle participate in additional reactions.…”

O 2 sensing, mitochondria and ROS signaling: The fog is lifting

“…As Δ ;Ψm is critical for the generation of ROS as well as for transport of proteins, ions and small molecules across the inner membrane, it is important to understand if and how that effect could be altering the O 2 sensing response. Important new insight into this question comes from recent studies by Orr et al, who used high throughput chemical screening to identify compounds capable of selectively limiting superoxide production by complex III 110 . The compounds identified in the initial screen were then subjected to further screening to eliminate those that were unselective for the Qo site of complex III, or that produced any impairment of bioenergetic function or Δ ;Ψm.…”

HIF1α and metabolic reprogramming in inflammation

“…Similarly to the PHD enzymes, FIH activity promotes HIF degradation. Antimycin-induced superoxide production was suppressed by small-molecule inhibitors, which concurrently inhibited HIF1α stabilization without directly affecting metabolism (31). Cells that lack mitochondria (known as ρ ο cells) failed to induce HIF1α accumulation in response to hypoxia (32); therefore, maintenance of mitochondrial membrane potential is essential not only for efficient bioenergetic function, but also for cell proliferation and oxygen sensing (33).…”