Biology subjects

Schneider, L. E.

Publications and source records attributed to Schneider, L. E..

2 recordsLinked to original sources

bioRxiv2026

Characterizing Mitochondrial Dysfunction Across Time in a Porcine model of Spinal Cord Injury

Spinal cord injury (SCI) can result in temporary or permanent alterations in sensory, motor, and autonomic functions as a result of primary mechanical damage to the spinal cord. Functional recovery is often limited due to persistent secondary injury mechanisms like inflammation, vascular breakdown, and cellular damage. Mitochondrial dysfunction is a key driver of secondary injury pathology, and while mitochondrial-targeted therapies have shown promise in rodent models of injury, functional improvements fail to translate to humans. Pigs are excellent models for understanding both the behavioral and molecular consequences of SCI because of their physiological similarity to humans, which could bridge the translational gap between rodent research and clinical implementation. To develop effective, mechanistic-based therapies, we must understand the molecular underpinnings of SCI using both male and female animal models with high translational fidelity at multiple time points after injury. To date, research on mitochondrial dysfunction following SCI has been limited to female rodent models measured acutely (6h-7d) after injury. Here, we studied mitochondrial dysfunction at three different time points in male pigs to establish a relative time course of mitochondrial impairment following SCI that may be therapeutically targeted to treat secondary complications of injury. We measured mitochondrial bioenergetic function and electron transport chain (ETC) complex activities, as well as qualified mitochondrial dynamics and oxidative damage acutely (2h), sub-acutely (24h), and chronically (9wk) after SCI in adult male pigs. The results show distinct patterns of mitochondrial dysfunction between time points with functional deficits occurring 2h post-SCI, increased mitochondrial fragmentation at 24h post-SCI, and mitochondrial recovery by 9wks post-SCI. These studies offer insight into mitochondrial changes across time in a clinically relevant animal model of SCI in hopes of bridging the translational research gap.

neuroscience↗

bioRxiv2025

Lysosomal cathepsin D regulates bone turnover through distinct mode of actions of the autophagy pathways in osteoblasts and osteoclasts

Insufficiency in nutrient availability, oxidative stress and autophagy failure are fundamental factors for the decline of bone mass and strength with aging. Accumulating evidence indicates that these factors affect normal autophagosomal or lysosomal activities which are the major force in clearance of aggregated or damaged proteins. Cathepsin D (CtsD), the principal lysosomal aspartate protease and a main endopeptidase, exists in the skeleton during development or homeostasis. However, the molecular and cellular mechanisms of CtsD mediated autophagosome or lysosome function in the skeletal homeostasis remain unclear. In the present study, we showed that deletion of CtsD dramatically decreased bone mass in the 3-week old mutant mice compared with their control littermates as indicated by decreased bone volume (BV), bone volume / total volume (BV/TV), bone surface (BS), trabecular number, trabecular thickness and increase trabecular separation in the microCT analysis. Histomorphometry analysis revealed that the phenotype was characterized by decreased osteoblast numbers, osteoblast surface/bone surface and mineral apposition rate, increased osteoclast numbers, osteoclast surface/bone surface and erosion surface/bone surface. At molecular level, siRNA medicated inactivation of CtsD in MC3T3E1 cells attenuated osteoblastic differentiation and downregulated LC3B expression, which was accompanied by decreased levels of P62, p-Akt and p-GSK3beta in osteoblasts. Intriguingly, inactivation of CtsD in RAW264.7 cells increased osteoclast differentiation with decreased LC3B expression but upregulated P62 level. This was accompanied by alterations in the formation of autophagosome and differential transcription profiles associated with the autophagy pathway during the differentiation of osteoblasts and osteoclasts. The results suggest that CtsD mediated autophagy pathway plays important roles in regulation of bone mass and homeostasis through distinct mode of actions in osteoblasts and osteoclasts, and CtsD may serve as a potential therapeutic target for the maintenance of bone mass.

cell biology↗