The germline coordinates mitokine signaling.

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

The extracellular matrix integrates mitochondrial homeostasis.

Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-ß response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.

The germline coordinates mitokine signaling.

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans , neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the WNT ligand EGL-20, which activate the mitochondrial unfolded protein response (UPR MT ) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-peripheral UPR MT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, like WNT and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPR MT activation. We also find that the germline tissue itself is essential in UPR MT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing.

The integrity of the nuclear envelope barrier relies on membrane remodeling by the ESCRTs, which seal nuclear envelope holes and contribute to the quality control of nuclear pore complexes (NPCs); whether these processes are mechanistically related remains poorly defined. Here, we show that the ESCRT-II/III chimera, Chm7, is recruited to a nuclear envelope subdomain that expands upon inhibition of NPC assembly and is required for the formation of the storage of improperly assembled NPCs (SINC) compartment. Recruitment to sites of NPC assembly is mediated by its ESCRT-II domain and the LAP2-emerin-MAN1 (LEM) family of integral inner nuclear membrane proteins, Heh1 and Heh2. We establish direct binding between Heh2 and the "open" forms of both Chm7 and the ESCRT-III, Snf7, and between Chm7 and Snf7. Interestingly, Chm7 is required for the viability of yeast strains where double membrane seals have been observed over defective NPCs; deletion of CHM7 in these strains leads to a loss of nuclear compartmentalization suggesting that the sealing of defective NPCs and nuclear envelope ruptures could proceed through similar mechanisms.

Border Safety: Quality Control at the Nuclear Envelope.

The unique biochemical identity of the nuclear envelope confers its capacity to establish a barrier that protects the nuclear compartment and directly contributes to nuclear function. Recent work uncovered quality control mechanisms employing the endosomal sorting complexes required for transport (ESCRT) machinery and a new arm of endoplasmic reticulum-associated protein degradation (ERAD) to counteract the unfolding, damage, or misassembly of nuclear envelope proteins and ensure the integrity of the nuclear envelope membranes. Moreover, cells have the capacity to recognize and triage defective nuclear pore complexes to prevent their inheritance and preserve the longevity of progeny. These mechanisms serve to highlight the diverse strategies used by cells to maintain nuclear compartmentalization; we suggest they mitigate the progression and severity of diseases associated with nuclear envelope malfunction such as the laminopathies.

ESCRTs breach the nuclear border.

The endosomal sorting complexes required for transport (ESCRT) are best known for their role in sorting ubiquitylated membrane proteins into endosomes. The most ancient component of the ESCRT machinery is ESCRT-III, which is capable of oligomerizing into a helical filament that drives the invagination and scission of membranes aided by the AAA ATPase, Vps4, in several additional subcellular contexts. Our recent study broadens the work of ESCRT-III by identifying its role in a quality control pathway at the nuclear envelope (NE) that ensures the normal biogenesis of nuclear pore complexes (NPCs). Here, we will elaborate on how we envision this mechanism to progress and incorporate ESCRT-III into an emerging model of nuclear pore formation. Moreover, we speculate there are additional roles for the ESCRT-III machinery at the NE that broadly function to ensure its integrity and the maintenance of the nuclear compartment.

Surveillance of nuclear pore complex assembly by ESCRT-III/Vps4.

The maintenance of nuclear compartmentalization by the nuclear envelope and nuclear pore complexes (NPCs) is essential for cell function; loss of compartmentalization is associated with cancers, laminopathies, and aging. We uncovered a pathway that surveils NPC assembly intermediates to promote the formation of functional NPCs. Surveillance is mediated by Heh2, a member of the LEM (Lap2-emerin-MAN1) family of integral inner nuclear membrane proteins, which binds to an early NPC assembly intermediate, but not to mature NPCs. Heh2 recruits the endosomal sorting complex required for transport (ESCRT)-III subunit Snf7 and the AAA-ATPase Vps4 to destabilize and clear defective NPC assembly intermediates. When surveillance or clearance is compromised, malformed NPCs accumulate in a storage of improperly assembled nuclear pore complexes compartment, or SINC. The SINC is retained in old mothers to prevent loss of daughter lifespan, highlighting a continuum of mechanisms to ensure nuclear compartmentalization.

The transmission of nuclear pore complexes to daughter cells requires a cytoplasmic pool of Nsp1.

Nuclear pore complexes (NPCs) are essential protein assemblies that span the nuclear envelope and establish nuclear-cytoplasmic compartmentalization. We have investigated mechanisms that control NPC number in mother and daughter cells during the asymmetric division of budding yeast. By simultaneously tracking existing NPCs and newly synthesized NPC protomers (nups) through anaphase, we uncovered a pool of the central channel nup Nsp1 that is actively targeted to the bud in association with endoplasmic reticulum. Bud targeting required an intact actin cytoskeleton and the class V myosin, Myo2. Selective inhibition of cytoplasmic Nsp1 or inactivation of Myo2 reduced the inheritance of NPCs in daughter cells, leading to a daughter-specific loss of viability. Our data are consistent with a model in which Nsp1 releases a barrier that otherwise prevents NPC passage through the bud neck. It further supports the finding that NPC inheritance, not de novo NPC assembly, is primarily responsible for controlling NPC number in daughter cells.

ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules.

The endoplasmic reticulum (ER) network is extremely dynamic in animal cells, yet little is known about the mechanism and function of its movements. The most common ER dynamic, termed ER sliding, involves ER tubule extension along stable microtubules (MTs). In this study, we show that ER sliding occurs on nocodazole-resistant MTs that are posttranslationally modified by acetylation. We demonstrate that high MT curvature is a good indicator of MT acetylation and show in live cells that ER sliding occurs predominantly on these curved, acetylated MTs. Furthermore, increasing MT acetylation by drug treatment increases the frequency of ER sliding. One purpose of the ER sliding on modified MT tracts could be to regulate its interorganelle contacts. We find that all mitochondria and many endosomes maintain contact with the ER despite the movements of each. However, mitochondria, but not endosomes, preferentially localize to acetylated MTs. Thus, different ER dynamics may occur on distinct MT populations to establish or maintain contacts with different organelles.