Jonathan R. Friedman

ER Tubules Mark Sites of Mitochondrial Division

Mitochondrial division occurs at positions where endoplasmic reticulum tubules contact mitochondria and mediate constriction. Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The endoplasmic reticulum (ER) and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.

Mitochondrial form and function

Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelles behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction.

ER sliding dynamics and ER–mitochondrial contacts occur on acetylated microtubules

Movement of the ER and mitochondria is coupled by limited interactions of the ER with a subset of posttranslationally modified microtubules.

The ER in 3D: a multifunctional dynamic membrane network

The endoplasmic reticulum (ER) is a large, singular, membrane-bound organelle that has an elaborate 3D structure with a diversity of structural domains. It contains regions that are flat and cisternal, ones that are highly curved and tubular, and others adapted to form contacts with nearly every other organelle and with the plasma membrane. The 3D structure of the ER is determined by both integral ER membrane proteins and by interactions with the cytoskeleton. In this review, we describe some of the factors that are known to regulate ER structure and discuss how this structural organization and the dynamic nature of the ER membrane network allow it to perform its many different functions.

ER exit sites are physical and functional core autophagosome biogenesis components.

ERES function is required for assembly of the autophagy machinery immediately downstream of the Atg1 kinase complex and is associated with formation of autophagosomes at every stage of the process. ERES are core components of the autophagy machinery for the biogenesis of autophagosomes.

Endoplasmic reticulum–endosome contact increases as endosomes traffic and mature

Endosomes do not traffic autonomously but instead associate with the ER membrane. ER tubules wrap around and maintain contact with both early and late endosomes by ER ring rearrangements. As endosomes mature, they increase the degree of their ER association, which suggests that the ER might play a role in endosomal maturation.

Universality of human microbial dynamics

The recent realization that human-associated microbial communities play a crucial role in determining our health and well-being1,2 has led to the ongoing development of microbiome-based therapies3 such as fecal microbiota transplantation4,5. Thosemicrobial communities are very complex, dynamic6 and highly personalized ecosystems3,7, exhibiting a high degree of inter-individual variability in both species assemblages8 and abundance profiles9. It is not known whether the underlying ecological dynamics, which can be parameterized by growth rates, intra- and inter-species interactions in population dynamics models10, are largely host-independent (i.e. “universal”) or host-specific. If the inter-individual variability reflects host-specific dynamics due to differences in host lifestyle11, physiology12, or genetics13, then generic microbiome manipulations may have unintended consequences, rendering them ineffectual or even detrimental. Alternatively, microbial ecosystems of different subjects may follow a universal dynamics with the inter-individual variability mainly stemming from differences in the sets of colonizing species7,14. Here we developed a novel computational method to characterize human microbial dynamics. Applying this method to cross-sectional data from two large-scale metagenomic studies, the Human Microbiome Project9,15 and the Student Microbiome Project16, we found that both gut and mouth microbiomes display pronounced universal dynamics, whereas communities associated with certain skin sites are likely shaped by differences in the host environment. Interestingly, the universality of gut microbial dynamics is not observed in subjects with recurrent Clostridium difficile infection17 but is observed in the same set of subjects after fecal microbiota transplantation. These results fundamentally improve our understanding of forces and processes shaping human microbial ecosystems, paving the way to design general microbiome-based therapies18.

MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture

The conserved MICOS complex functions as a primary determinant of mitochondrial inner membrane structure. We address the organization and functional roles of MICOS and identify two independent MICOS subcomplexes: Mic27/Mic10/Mic12, whose assembly is dependent on respiratory complexes and the mitochondrial lipid cardiolipin, and Mic60/Mic19, which assembles independent of these factors. Our data suggest that MICOS subcomplexes independently localize to cristae junctions and are connected via Mic19, which functions to regulate subcomplex distribution, and thus, potentially also cristae junction copy number. MICOS subunits have non-redundant functions as the absence of both MICOS subcomplexes results in more severe morphological and respiratory growth defects than deletion of single MICOS subunits or subcomplexes. Mitochondrial defects resulting from MICOS loss are caused by misdistribution of respiratory complexes in the inner membrane. Together, our data are consistent with a model where MICOS, mitochondrial lipids and respiratory complexes coordinately build a functional and correctly shaped mitochondrial inner membrane. DOI: http://dx.doi.org/10.7554/eLife.07739.001

MICOS and phospholipid transfer by Ups2–Mdm35 organize membrane lipid synthesis in mitochondria

Mitochondria exert critical functions in lipid metabolism and promote the synthesis of major constituents of cellular membranes, such as phosphatidylethanolamine (PE). Here, Aaltonen et al. demonstrate that two pathways mediate PE synthesis: Ups2–Mdm35–dependent lipid transfer and MICOS-dependent membrane apposition.

Identification of Non-dot/icm Suppressors of the Legionella pneumophila dotL Lethality Phenotype

Legionella pneumophila, a causative agent of bacterial pneumonia, survives inside phagocytic cells by avoiding rapid targeting to the lysosome. This bacterium utilizes a type IVB secretion system, encoded by the dot/icm genes, to replicate inside host cells. DotL, a critical component of the Dot/Icm secretion apparatus, functions as the type IV coupling protein. In contrast to most dot/icm genes, which are dispensable for growth on bacteriological media, dotL is required for the viability of wild-type L. pneumophila. Previously we reported that DeltadotL lethality could be suppressed by inactivation of the Dot/Icm complex via mutations in other dot/icm genes. Here we report the isolation of non-dot/icm suppressors of this phenotype. These DeltadotL suppressors include insertions that disrupt the function of the L. pneumophila homologs of cpxR, djlA, lysS, and two novel open reading frames, lpg0742 and lpg1594, that we have named ldsA and ldsB for lethality of DeltadotL suppressor. In addition to suppressing DeltadotL lethality, inactivation of these genes in a wild-type strain background causes a range of defects in L. pneumophila virulence traits, including intracellular growth, implicating these factors in the proper function of the Dot/Icm complex. Consistent with previous data showing a role for the cpx system in regulating expression of several dot/icm genes, the cpxR insertion mutant produced decreased levels of three Dot/Icm proteins, DotA, IcmV, and IcmW. The remaining four suppressors did not affect the steady-state levels of any Dot/Icm protein and are likely to represent the first identified factors necessary for assembly and/or activation of the Dot/Icm secretion complex.