Dendrite architecture determines mitochondrial distribution patterns in vivo.

Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules-which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness-predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.

Morphology and Transport in Eukaryotic Cells.

Transport of intracellular components relies on a variety of active and passive mechanisms, ranging from the diffusive spreading of small molecules over short distances to motor-driven motion across long distances. The cell-scale behavior of these mechanisms is fundamentally dependent on the morphology of the underlying cellular structures. Diffusion-limited reaction times can be qualitatively altered by the presence of occluding barriers or by confinement in complex architectures, such as those of reticulated organelles. Motor-driven transport is modulated by the architecture of cytoskeletal filaments that serve as transport highways. In this review, we discuss the impact of geometry on intracellular transport processes that fulfill a broad range of functional objectives, including delivery, distribution, and sorting of cellular components. By unraveling the interplay between morphology and transport efficiency, we aim to elucidate key structure-function relationships that govern the architecture of transport systems at the cellular scale.

Cumulative Mortality and Factors Associated With Outcomes of Mucormycosis After COVID-19 at a Multispecialty Tertiary Care Center in India.

Importance: An outbreak of COVID-19-associated rhino-orbitocerebral mucormycosis (CAM) has occurred in many parts of the world. Although the clinical profile and risk factors for CAM have been studied, cumulative mortality and its risk factors have not. Objective: To report the cumulative mortality rates at different times in cases with CAM and identify risk factors for CAM-associated mortality. Design, Setting, and Participants: This retrospective case-control study was conducted from March 1 to May 30, 2021, in a tertiary care multispecialty hospital in western India. All patients diagnosed with CAM and with a minimum follow-up of 30 days or those who died before 30 days due to CAM were included. Main Outcomes and Measure: Cumulative mortality in CAM using survival analysis. Results: A total of 73 consecutive patients with CAM with a mean (SD) age of 53.5 (12.5) years were included in the analysis, of whom 48 (66%) were men. CAM developed at a median of 28 (IQR, 15-45; range, 4-90) days after recovery from COVID-19. Of the 73 patients with CAM, 26 (36%) died; the cumulative probability of death was 26% (95% CI, 16%-41%) at day 7 and doubled to 53% (95% CI, 39%-69%) at day 21. Sinus debridement was performed in 18 of 51 patients (35%), and 5 of 52 (10%) underwent exenteration, whereas intravenous lyophilized amphotericin B was administered to 48 patients (66%). A multivariate Cox proportional hazards regression analysis showed that receiving mechanical ventilation in the past was associated with a nearly 9-fold increased risk of death (hazard ratio [HR], 8.98; 95% CI, 2.13-38.65; P = .003), and patients who had visual acuity of light perception or better had a 46% lower risk of death (HR, 0.56; 95% CI, 0.32-0.98; P = .04). Intravenous amphotericin B administration was associated with a reduced rate of exenteration (0 vs 5 of 25 [20%]; P < .001). On multivariate analysis, those who received intravenous amphotericin B had a 69% reduced risk of death (HR, 0.31; 95% CI, 0.06-1.43; P = .13). Conclusions and Relevance: These findings suggest that the mortality rate after rhino-orbitocerebral mucormycosis is high and that a subgroup of patients with severe COVID-19 or presenting with severe orbital disease are more likely to die within 10 days of admission.

Optimizing mitochondrial maintenance in extended neuronal projections.

Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mitochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, a key aspect underlying many neurodegenerative disorders.

Spatial control of neuronal metabolism through glucose-mediated mitochondrial transport regulation.

Eukaryotic cells modulate their metabolism by organizing metabolic components in response to varying nutrient availability and energy demands. In rat axons, mitochondria respond to glucose levels by halting active transport in high glucose regions. We employ quantitative modeling to explore physical limits on spatial organization of mitochondria and localized metabolic enhancement through regulated stopping of processive motion. We delineate the role of key parameters, including cellular glucose uptake and consumption rates, that are expected to modulate mitochondrial distribution and metabolic response in spatially varying glucose conditions. Our estimates indicate that physiological brain glucose levels fall within the limited range necessary for metabolic enhancement. Hence mitochondrial localization is shown to be a plausible regulatory mechanism for neuronal metabolic flexibility in the presence of spatially heterogeneous glucose, as may occur in long processes of projection neurons. These findings provide a framework for the control of cellular bioenergetics through organelle trafficking.

Extra Nodal Rosai-Dorfman Disease (Sinus Histiocytosis with Massive Lymphadenopathy) Presenting as Asymmetric Bilateral Optic Atrophy : An Atypical Ocular Presentation.

Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy, SHML) is a rare, non-hereditary, benign histiocytic proliferative disorder, presenting as painless bilateral cervical lymphadenopathy, with systemic symptoms. Extra nodal manifestations have been reported in 28-43 % cases with rare ocular involvement. We report a case of a 57 year old female presenting with gradual progressive decrease of vision OU since 8 months associated with epistaxis. Fundus examination revealed established optic atrophy in right eye with features of chronic papilloedema in left eye suggestive of compressive lesion. CT of brain, paranasal sinuses confirmed the presence of homogenously enhancing mass in left ethmoid sinus, left sphenoid sinus extending into suprasellar region. The biopsy of this mass revealed extra nodal SHML with tissue sections being S100 and CD68 positive with emperipolesis noted. Here we describe this atypical ocular presentation of extra nodal SHML to highlight that this rare disease can manifest as an aggressive sight threatening entity, even in older age group.