Multilevel impairment of mitochondrial respiration in inclusion body myositis.

Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise‐Induced Redox Responses in Human Skeletal Muscle

ABSTRACT Redox imbalances and mitochondrial dysfunction are key contributors to age‐related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60‐min of high‐intensity knee‐extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre‐ and post‐exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise‐induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise‐induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

Differential Regulation of Mitochondrial and Autophagy Markers in a Mouse Model of Cardioskeletal Myopathy

These findings reveal pronounced tissue divergence in mitochondrial remodeling in DARS2-related cardioskeletal myopathy and underscore caution when interpreting colchicine-based autophagy flux assays in heart versus skeletal muscle.

Preserved mitochondrial respiration in presence of oxidative stress and reduced mitochondrial mass after 10-day bed rest in older adults.

Bioenergetic profiling of fresh human kidney tissue reveals compensatory metabolic adaptation and intrinsic mitochondrial dysfunction in diabetes

The kidney is a highly energetic organ, requiring substantial ATP production through mitochondrial oxidative phosphorylation to support tubular reabsorption. Metabolic reprogramming and impaired mitochondrial function are implicated in diabetic kidney disease, yet direct assessment of mitochondrial respiratory flux in the human kidney has been constrained by limited access to freshly obtained tissue. Consequently, much of the evidence supporting altered renal mitochondrial function in diabetes derives from animal models that do not fully recapitulate the human condition. We established a workflow for real-time bioenergetic profiling of fresh kidney cortex obtained during nephrectomy from living individuals with diabetes and preserved kidney function. Mitochondrial respiration, electron transport system activity and tubular mitochondrial morphology were compared with age- and sex-matched, histopathologically normal non-diabetic controls. High-resolution respirometry revealed increased mitochondrial respiratory flux in permeabilised diabetic kidney cortex. In contrast, mitochondria isolated from the same tissue exhibited reduced respiratory capacity and impaired complex I activity. Quantitative analysis of tubular cells demonstrated increased mitochondrial volume density together with greater mitochondrial fragmentation in diabetes. These findings reveal that the human kidney undergoes substantial metabolic adaptation early in diabetes, before measurable loss of kidney function. Increased tissue-level respiratory flux despite intrinsic mitochondrial impairment suggests that expansion and remodelling of the mitochondrial network may initially compensate for reduced organelle efficiency and sustain the kidney’s high energetic demands. This compensatory state may, however, increase metabolic stress and vulnerability to subsequent kidney injury. To our knowledge, this study provides the first direct tissue-level functional evidence that mitochondrial metabolism is reprogrammed in the human kidney in diabetes before measurable kidney dysfunction develops. It defines an early bioenergetic signature characterised by tissue hypermetabolism despite impaired mitochondria-specific respiratory capacity, challenging the concept that diabetes produces a uniform decline in renal mitochondrial function. Failure to sustain this adaptive state may represent a critical transition towards diabetic kidney disease. GRAPHICAL ABSTRACT One Sentence Summary Diabetes drives early metabolic reprogramming of the human kidney before measurable kidney dysfunction

Novel in vivo measurement of muscle total carnitine concentration reveals potential mechanism linking mitochondrial dysfunction and lipid accumulation

Free carnitine is essential to mitochondrial health by buffering the free acetyl-CoA pool and thereby maintaining energy production. It is also responsible for transporting long-chain fatty acids into the mitochondria for oxidation. Almost all the body's carnitine is in muscle, and plasma concentrations do not reflect tissue content, but there are as yet no non-invasive techniques to assess muscle total or free carnitine. Here we describe a novel non-invasive postprocessing method, using standard 1H magnetic resonance spectroscopy data, for quantifying muscle total and free carnitine concentrations, which includes an orientation- visibility and spectral fitting component, and consideration of interfering metabolites. We demonstrate the importance of the orientation correction even within one muscle group (accounting for up to 1.9-fold difference within one muscle group and 2.9-fold difference in signal between muscles), show its good reproducibility (CoV 8-12%), and validate the results with mass spectrometry measurements in muscle biopsy samples. We apply this method in a group of patients with genetic mitochondrial disease, to investigate the relationship between mitochondrial dysfunction and muscle lipid accumulation. As predicted muscle total and free carnitine were lower in patients with disease and correlated with the degree of mitochondrial dysfunction and lipid accumulation. Further, robust spatial correlations of total carnitine and muscle lipid imply heterogeneity in mitochondrial function. Our findings suggest that increasing muscle carnitine stores could ameliorate the metabolic effects of and disorders related to mitochondrial dysfunction. Furthermore, it has not usually been known in supplementation studies whether l-carnitine actually reached the target tissue. We suggest that this novel method has significant potential for informing on physiology and pathophysiology, and as a biomarker in monitoring treatment response, investigative drug discovery, and personalised medicine.

Primary Mitochondrial-Disorders-Associated Nephropathy in Adulthood

Oxidative phosphorylation (OXPHOS) is the main source of cellular adenosine triphosphate (ATP) production and depends on proteins encoded by both mitochondrial and nuclear DNA (nDNA). Pathogenic variants affecting this dual genetic control cause primary mitochondrial disorders (MIDs), which follow either maternal inheritance when they affect mitochondrial DNA (mtDNA) or autosomal inheritance when they affect nuclear-encoded mitochondrial proteins. Once considered predominantly pediatric conditions, these disorders are increasingly recognized in adults where their clinical presentation is heterogeneous and frequently underdiagnosed, requiring the involvement of various medical specialties.Because of their high energy requirements, kidneys are particularly vulnerable to primary MIDs. Tubular epithelial cells rely on OXPHOS for solute transport, whereas podocytes require sustained ATP production to preserve the glomerular filtration barrier. Although kidney involvement in adult primary MIDs has long been regarded as rare, emerging data indicate that primary MIDs–associated nephropathy (MIDAN) is more common than previously appreciated, yet remains under-recognized, as a cause of adult kidney disease. Renal manifestations include a broad spectrum of glomerular disorders—predominantly focal segmental glomerulosclerosis (FSGS), often associated with diabetes mellitus and sensorineural hearing impairment—as well as tubulo-interstitial nephritis (TIN), which may present as an isolated renal phenotype or as part of a multisystemic disorder.Advances in next-generation sequencing, including mitochondrial genome sequencing and exome or whole-genome sequencing, are transforming the diagnostic approach to MIDAN. Improved recognition of mitochondrial etiologies in adults with unexplained glomerular or tubulo-interstitial kidney disease is essential to optimize diagnosis, management, and genetic counseling.