Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion.

We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/HO, providing: i) mitochondria-to-plasma-membrane redox signaling, closing K-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated HO-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLAγ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLAγ/PNPLA8-knockout mice/PIs.

Antioxidant Role and Cardiolipin Remodeling by Redox-Activated Mitochondrial Ca-Independent Phospholipase Aγ in the Brain.

Mitochondrial Ca-independent phospholipase Aγ (iPLAγ/PNPLA8) was previously shown to be directly activated by HO and release free fatty acids (FAs) for FA-dependent H transport mediated by the adenine nucleotide translocase (ANT) or uncoupling protein 2 (UCP2). The resulting mild mitochondrial uncoupling and consequent partial attenuation of mitochondrial superoxide production lead to an antioxidant effect. However, the antioxidant role of iPLAγ in the brain is not completely understood.

Antioxidant Synergy of Mitochondrial Phospholipase PNPLA8/iPLA2γ with Fatty Acid-Conducting SLC25 Gene Family Transporters.

Patatin-like phospholipase domain-containing protein PNPLA8, also termed Ca-independent phospholipase A2γ (iPLA2γ), is addressed to the mitochondrial matrix (or peroxisomes), where it may manifest its unique activity to cleave phospholipid side-chains from both sn-1 and sn-2 positions, consequently releasing either saturated or unsaturated fatty acids (FAs), including oxidized FAs. Moreover, iPLA2γ is directly stimulated by HO and, hence, is activated by redox signaling or oxidative stress. This redox activation permits the antioxidant synergy with mitochondrial uncoupling proteins (UCPs) or other SLC25 mitochondrial carrier family members by FA-mediated protonophoretic activity, termed mild uncoupling, that leads to diminishing of mitochondrial superoxide formation.