Golgi-derived PI ( 4 ) P-containing vesicles drive late steps of mitochondrial division

Abstract

Mitochondrial plasticity is a key regulator of cell fate decisions. Mitochondrial division involves Dynamin-related protein-1 (Drp1) oligomerization, which constricts membranes at endoplasmic reticulum (ER) contact sites. The mechanisms driving the final steps of mitochondrial division are still unclear. Here, we found that microdomains of phosphatidylinositol 4-phosphate [PI(4)P] on trans-Golgi network (TGN) vesicles were recruited to mitochondria–ER contact sites and could drive mitochondrial division downstream of Drp1. The loss of the small guanosine triphosphatase ADP-ribosylation factor 1 (Arf1) or its effector, phosphatidylinositol 4-kinase IIIβ [PI(4)KIIIβ], in different mammalian cell lines prevented PI(4)P generation and led to a hyperfused and branched mitochondrial network marked with extended mitochondrial constriction sites. Thus, recruitment of TGN-PI(4)P–containing vesicles at mitochondria–ER contact sites may trigger final events leading to mitochondrial scission.

Mitochondrial dynamics during spermatogenesis

“…In mammals, four receptors recruit cytosolic DRP1 to the mitochondrial outer membrane: mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51; encoded by Mief2 and Mief1, respectively), and mitochondrial fission 1 (FIS1) (Chan, 2012). Dynamin-2 (DNM2) has been proposed to act at a terminal step following DRP1 constriction (Lee et al, 2016), but this idea was recently challenged (Fonseca et al, 2019;Kamerkar et al, 2018;Nagashima et al, 2020). Lysosomes (Wong et al, 2018) and Golgi-derived vesicles (Nagashima et al, 2020) have also been implicated in mitochondrial fission, but how they interact with the fission machinery remains to be resolved.…”

“…Dynamin-2 (DNM2) has been proposed to act at a terminal step following DRP1 constriction (Lee et al, 2016), but this idea was recently challenged (Fonseca et al, 2019;Kamerkar et al, 2018;Nagashima et al, 2020). Lysosomes (Wong et al, 2018) and Golgi-derived vesicles (Nagashima et al, 2020) have also been implicated in mitochondrial fission, but how they interact with the fission machinery remains to be resolved.…”

Drosophila phosphatidylinositol-4 kinase fwd promotes mitochondrial fission and can suppress Pink1/parkin phenotypes

“…PI(4)P is one of the most abundant phosphoinositides, which is usually concentrated in the trans-Golgi network [ 35 ]; thus, the mechanism by which PI(4)P may influence mitochondrial dynamics is not immediately obvious. However, while this manuscript was in preparation, Nagashima and colleagues reported that Golgi-derived PI(4)P-containing vesicles were required for the final stages of mitochondrial fission [ 3 ]. In that study, the authors found that loss of PI(4)KIIIβ led to hyperfusion and increased branching of the mitochondrial network, consistent with what we observed here.…”

“…Maintaining an appropriate balance of fission and fusion, as well as transport dynamics, is crucial for cellular health and survival as mutations in many of the core components cause severe neurological conditions in humans and model organisms [ 2 ]. Recently, a role for phosphatidylinositol 4-phosphate [PI(4)P] in mitochondrial fission has been elucidated in cultured cells [ 3 ], but the in vivo consequences have not yet been described.…”

Direct trafficking pathways from the Golgi apparatus to the plasma membrane

“…PI(4)KIIIβ is also involved in the recruitment of the small G protein Rab11a [174,175] shown to be important for tsVSV-G trafficking from the trans-Golgi to the plasma membrane [176]. PI(4)KIIIβ was shown to have an important role in mitochondrial scission generating PI(4)P on trans-Golgi derived vesicles after recruitment by Arf1 [177]. These vesicles are targeted to mitochondria-ER contact sites and are thought to drive mitochondrial division downstream of Drp1 (Dynamin-related protein-1).…”