piRNA-Associated Germline Nuage Formation and Spermatogenesis Require MitoPLD Profusogenic Mitochondrial-Surface Lipid Signaling

Abstract

Summary The mammalian Phospholipase D MitoPLD facilitates mitochondrial fusion by generating the signaling lipid phosphatidic acid (PA). The Drosophila MitoPLD homolog Zucchini (Zuc), a proposed cytoplasmic nuclease, is required for piRNA generation, a critical event in germline development. We show that Zuc localizes to mitochondria and has MitoPLD-like activity. Conversely, MitoPLD−/− mice exhibit the meiotic arrest, DNA damage, and male sterility characteristic of mice lacking piRNAs. The primary function of MitoPLD appears to be the generation of mitochondrial-surface PA. This PA in turn recruits the phosphatase Lipin 1, which converts PA to diacylglycerol and promotes mitochondrial fission, suggesting a mechanism for mitochondrial morphology homeostasis. MitoPLD and Lipin 1 have opposing effects on mitochondria length and on intermitochondrial cement (nuage), a structure found between aggregated mitochondria that is implicated in piRNA generation. We propose that mitochondrial-surface PA generated by MitoPLD / Zuc recruits or activates nuage components critical for piRNA production.

Rhabdomyolysis-Associated Mutations in Human LPIN1 Lead to Loss of Phosphatidic Acid Phosphohydrolase Activity

“…WT lipin 1 had approx. sixfold higher V max than p.Leu635Pro and p.Arg725His with no change in K m lead to recurrent rhabdomyolysis (Bennett 2010;Zutt et al 2014), and lipin 1 PAP activity impacts mitochondrial function by regulating fission and fusion (Huang et al 2011). Very recently, it was reported that lipin 1 deficiency in muscle of mice caused myopathy via impaired autophagy, and a link between lipin 1-mediated PAP activity and autolysosome maturation was defined (Zhang et al 2014).…”

piRNA-mediated transgenerational inheritance of an acquired trait

“…Aging is known to affect mitochondrial physiology (Schwarze et al 1998;Das et al 2001). Potential relationships have been recently described between mitochondria and primary piRNA biogenesis (Haase et al 2010;Olivieri et al 2010;Huang et al 2011;Watanabe et al 2011). Hence, a putatively improved primary piRNA production might explain why aged ovaries produce more secondary I-element piRNAs.…”

mRNP granules

“…Interaction of IMC components with phosphatidic acid was suggested as a means to concentrate and nucleate granule formation. 61,62 It will be interesting to determine if similar mechanisms are used by other mRNP granules.…”

“…This later phenomenon also holds true for specific mRNAs, which exit stress granules and enter translation during the recovery phase. 62,63 Dendritic P-bodies also disassemble upon synaptic activation, 15 which may reflect entry of mRNAs into translation. mRNP granules could also be disassembled via mRNA decay, which is most likely relevant to P-bodies, given their enrichment for the decay machinery, the detection of mRNA decay intermediates within, and a correlative increase in P-body numbers when hard to degrade substrates are present.…”