Biology subjects

Lopez, E. G.

Publications and source records attributed to Lopez, E. G..

4 recordsLinked to original sources

bioRxiv2024

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes

Background & AimsAging is associated with a significant decline in mitochondrial function in the liver, leading to an increased risk of liver disease. This study examines age-related changes in the mitochondrial structure of human and murine livers using a combination of Serial Block-Face Scanning Electron Microscopy (SBF-SEM) and mass spectrometry approaches. MethodsThis study integrates mitochondrial structure analysis in a murine model with an analysis of liver architecture, lipogenesis, and genetically regulated gene expression in human cohorts. We explored the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex using SBF-SEM, three-dimensional reconstruction with Amira software, and mass spectrometry techniques. ResultsAging leads to a reduction in mitochondrial size and complexity, resulting in changes in the metabolomic and lipidomic profiles of murine liver cells that are comparable to those observed in aged human samples. We find that genetically modeled expression of MICOS complex genes OPA1 and CHCHD3 is associated with chronic liver disease phenotypes within a large biobank population. Furthermore, we observed dysregulated mitochondrial calcium handling and increased oxidative stress due to the disruption of the MICOS complex. ConclusionOur study highlights the age-associated decline in mitochondrial complexity and metabolic regulation within the aging murine liver and the human population. We have identified that these changes are partially attributable to the age-related loss of the MICOS complex. Impact and implicationsThis study offers new insights into the changes to mitochondrial ultrastructure that occur during aging. Using SBF-SEM, the quantification of young and aged murine mitochondrial structure was performed, which had previously been an underexplored avenue for measuring mitochondrial changes. The discovery of mitochondrial ultrastructural changes, in conjunction with measurements of age-associated metabolic alterations and gene association data, provides a model for how changes in MICOS expression may modulate age-related impairment of hepatic mitochondria. These results provide a new model by which changes in MICOS protein expression may both cause and be a potential therapeutic target for age-related impairment in hepatic function. HighlightsDecreased modeled expression of CHCHD3 in individuals of European genetic ancestry is linked to liver transplant and cirrhosis, while decreased modeled expression of OPA1 in individuals of African genetic ancestry is associated with chronic liver disease and cirrhosis. Aging alters liver lipid accumulation, MICOS mRNA levels, and disease markers. Aging reduces the volume and complexity of murine liver ultrastructure. Aging and diet significantly alter the MICOS complex in mice. Knockdown of Mic60 and Chchd6 lowers Ca2+ uptake, retention, and induces oxidative stress in HepG2 cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/599846v3_ufig1.gif" ALT="Figure 1000"> View larger version (47K): org.highwire.dtl.DTLVardef@1cdd61corg.highwire.dtl.DTLVardef@a3fb74org.highwire.dtl.DTLVardef@1d1ad36org.highwire.dtl.DTLVardef@c2e55f_HPS_FORMAT_FIGEXP M_FIG C_FIG Liver aging causes metabolic, lipidomic, and mitochondrial structural alterations, reflecting age-dependent losses in the MICOS complex. Key components of the MICOS complex (MIC60, CHCHD3 and CHCHD6) are illustrated.

physiology↗

bioRxiv2022

OPA1 Downregulation in Skeletal Muscle Induces MERC formation in an ATF4-Dependent Manner

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

biophysics↗

bioRxiv2022

3D Reconstructions of Mouse Skeletal Muscle and Heart Muscle Reveal a Decrease in the MICOS Complex and Altered Mitochondrial Networks

BackgroundDuring aging, muscle gradually undergoes loss of function including sarcopenia, losing mass, strength, endurance, and oxidative capacity. While mitochondrial aging is associated with decreased mitochondrial capacity, the genes associated with morphological changes in mitochondria during aging still require further elucidation. Furthermore, it is not completely understood how 3D mitochondrial structures are altered during aging in skeletal muscle and cardiac tissues. MethodsWe measured changes in mitochondrial morphology and mitochondrial complexity during the aging of murine gastrocnemius, soleus, and cardiac tissues using serial block face- scanning electron microscopy and 3D reconstruction. Lipidomic and metabolomic analysis elucidated concomitant changes associated with aging. We also used qPCR, transmission electron microscopy quantification, Seahorse Analyzer, and metabolomics to evaluate changes in mitochondria morphology and function upon loss of the MICOS complex. ResultsWe identified significant changes in 3D mitochondrial size and network configuration in murine gastrocnemius, soleus, and cardiac tissue during aging. These changes were concomitant with loss of mitochondria contact site and cristae organizing system (MICOS) gene expression during aging. Mitochondrial morphology was similar between aged mice and young mice. We show an age-related loss of the MICOS complex (Chchd3, chchd6, and Mitofilin) while their knockout results in alterations in mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we perform cellular metabolic profiling of young and aged tissues. Metabolomics and lipidomics showed profound alterations, including in membrane integrity, that support our observations of age-related changes in these muscle tissues. DiscussionIn tandem, our data suggest a relationship between the MICOS complex and aging, which could be linked to disease states with further 3D reconstruction studies. Our study highlights the importance of understanding tissue-dependent 3D mitochondrial phenotypical changes which occur across aging with evolutionary conservation between Drosophila and murine models. Graphical Abstract

biophysics↗

bioRxiv2021

Using a Champion-Oriented Mindset to Overcome the Challenges of Graduate School

Despite efforts to increase diversity, a glaring underrepresentation of minorities (URM) persists in the fields of science, technology, engineering, and mathematics (STEM). Graduate school can be a stressful step in the STEM pipeline, especially for students previously unaware of the structure and challenges of post-graduate education. To promote successful minority participation in STEM and prepare prospective students for the impending challenges of graduate school, we developed a workshop based on the mentoring and fostering of a champion-oriented mindset entitled, "The Trials and Tribulations of Graduate School: How Do You Make an Impact?". We administered the workshop to a cohort of university undergraduates and conducted pre- and post-workshop surveys to measure students perceived need for instruction on specific workshop topics. The results suggest that the workshop was well received by the students and provided information that they considered helpful to help navigate the graduate school process.

scientific communication and education↗