Biology subjects

Kramer, P. A.

Publications and source records attributed to Kramer, P. A..

3 recordsLinked to original sources

bioRxiv2026

Lactylation landscape of mitochondrial proteins in myocardial infarction

Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease. HighlightsO_LIMyocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins. C_LIO_LIAZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation. C_LIO_LIDistinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed. C_LIO_LIAZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/718938v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@b5a7b3org.highwire.dtl.DTLVardef@14ea92org.highwire.dtl.DTLVardef@1343a29org.highwire.dtl.DTLVardef@1d67716_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

cell biology↗

bioRxiv2025

Hip stabilization in an australopithecine-like hip: the influence of shape on muscle activation

Hip stabilization through muscular activation of the gluteals is a key feature of hominin walking, but the role of pelvic shape on muscular activation remains uncertain. Coupled with this is the uncertainty regarding whether or not the kinematics and kinetics of modern humans are appropriate proxies for the patterns in extinct hominins. In this work we treat modern human kinematics and kinetics as a null hypothesis by applying them to musculoskeletal models with modern human-like and australopithecine-like hips and examine the resulting joint reaction and muscle forces. We test the prediction that the hip functional complex that includes biacetabular breadth, femoral neck length, and iliac blade flare produces hip abductor muscle activations and hip joint reactions that are similar in the modern human- and australopithecine-like forms. Using previously developed musculoskeletal models that approximate gluteus maximus with twelve muscle elements, gluteus medius with twelve, and gluteus minimus with three, we calculated joint reaction and muscle forces using inverse dynamics analyses and a muscle redundancy algorithm. We used data from ten individuals who walked at their normal velocity. We found that the shape of the australopithecine-like pelvis produces absolutely higher muscle activations in gluteus medius and gluteus minimus, but lower muscle activations across a long period of stance in gluteus maximus compared to the modern human-like pelvis when kinematics and size are held constant. Hip joint reaction forces are similarly heterogeneous: the australopithecine-like hip exhibits lower forces in the direction of travel but higher in the vertical. These results suggest that, while the australopithecine-like pelvis is compatible with human walking patterns, influences on pelvic shape other than accommodating muscle and joint reaction forces during walking are present.

evolutionary biology↗

bioRxiv2019

Mitochondrial protein interaction landscape of SS-31

Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy. Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

systems biology↗