Disrupted Mitochondria May Accelerate Skeletal Aging
A new study reveals how mitochondrial dysfunction causes metabolic shifts in cartilage, triggering early skeletal aging.
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A malfunction in mitochondria’s energy system doesn’t just slow cells down – it may also trigger early-onset skeletal aging.
A new study from researchers at the University of Cologne, published in Science Advances, found that developmental disruptions in mitochondrial respiration can reprogram cartilage metabolism.
The expanding role of mitochondria in skeletal health
Mitochondria are well-known as the powerhouses of the cell, vital for converting nutrients into ATP through cellular respiration. However, recently it has become clear that their role extends far beyond energy metabolism. In addition to fueling cellular activity, mitochondria generate the building blocks needed for biosynthetic processes, including the synthesis of proteins, lipids and components of the extracellular matrix (ECM) – all critical for the growth and maintenance of skeletal tissue.
Disorders that impair mitochondrial function often involve early-onset skeletal problems, such as stunted growth and premature cartilage degeneration. Despite this link, the molecular mechanisms connecting mitochondrial dysfunction to skeletal aging have remained unclear. Earlier research has focused on the energy deficits caused by mitochondrial impairment, without considering how these disruptions affect the broader metabolic landscape of cartilage cells.
Recent work has begun to fill in these gaps. Growth plate cartilage – a tissue central to bone elongation during childhood – undergoes a unique metabolic transition after birth, shifting from glycolysis to oxidative phosphorylation. Previous studies in mouse models have shown that when this shift is disrupted, skeletal aging accelerates and growth plates close prematurely.
Glycolysis
A cellular process that breaks down glucose into pyruvate, generating small amounts of energy (ATP) and intermediates used in other metabolic pathways.
Oxidative phosphorylation
A process that occurs in mitochondria where energy from nutrients is used to produce large amounts of ATP, the cell’s main energy currency.
The new study used a genetically modified mouse model to explore how developmental impairments in mitochondrial respiration reshape cellular metabolism and trigger early skeletal degeneration.
Mouse model reveals the metabolic roots of cartilage aging
The mouse model was encoded with cartilage-specific expression of a mutated version of the mitochondrial helicase gene Twinkle. This mutation impairs mitochondrial DNA replication, leading to disruption of the mitochondrial respiratory chain (mtRC) – a key system for producing cellular energy and metabolic precursors.
The team combined several advanced techniques, including histological analysis of cartilage, metabolic profiling using mass spectrometry, stable isotope tracing with 13C-labeled glucose and glutamine, phosphoproteomic screening to identify changes in protein signaling and electron microscopy to assess cellular structure.
When mtRC function was impaired, the cells rerouted their metabolic activity through a reverse segment of the tricarboxylic acid (TCA) cycle – a process that supports the production of amino acids needed for growth. While this adaptation initially helps the tissue cope with stress, it can lead to persistent overproduction of amino acids and chronic activation of a signaling pathway called mTORC1.
The tricarboxylic acid (TCA) cycle
Also known as the Krebs cycle, this is a central metabolic pathway that generates energy and key building blocks by breaking down molecules derived from food.
Stable isotope tracing showed increased incorporation into TCA intermediates like malate and citrate in a reverse (reductive) direction, confirming the metabolic rerouting under mitochondrial dysfunction.
This altered metabolism stimulated the biosynthesis of key amino acids such as glycine, proline and aspartate, supporting the increased demand for protein synthesis during cartilage growth – but ultimately driving pathological mTORC1 activation.
This overactivation of mTORC1, which normally helps regulate cell growth in response to nutrients, disrupted essential processes like autophagy and impaired the secretion of ECM components. Even under nutrient-depleted conditions, mutant chondrocytes continued to display mTORC1 activity, suggesting that elevated intracellular amino acid levels alone were sufficient to maintain signaling, independent of external cues.
Autophagy
A process by which cells recycle damaged components and maintain cellular health, particularly under stress or nutrient deprivation.
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Proteomic analysis revealed abnormal accumulation of matrix proteins such as collagen IX and thrombospondin 1, and electron microscopy found disrupted structure in the endoplasmic reticulum and Golgi apparatus – organelles essential for protein processing and secretion.
Eventually, the cartilage cells began to die, and the tissue showed clear signs of premature aging.
The team found that supplementing cells with nicotinamide mononucleotide (NMN), a compound that helps restore cellular redox balance, improved cell survival under stress.
Cellular redox balance
The equilibrium between oxidizing and reducing agents in a cell. This balance is essential for energy production and metabolic function, and when disrupted, it can lead to oxidative stress and impaired cellular processes.
“Redox imbalances are key targets to restore chondrocyte survival and to prevent cartilage degeneration,” the authors said.
Targeting mitochondrial metabolism to delay skeletal degeneration
Rather than focusing solely on energy loss, the findings of the study point to a more complex picture involving maladaptive shifts in cell metabolism.
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By establishing a direct link between mitochondrial impairment and disrupted biosynthetic signaling, the results open up new avenues for potential intervention.
“The fundamental processes identified here could establish the basis for new treatment strategies to influence cartilage degeneration and skeletal aging in the context of mitochondrial disorders at an early stage,” said corresponding author Dr. Bent Brachvogel, a principal investigator at the University of Cologne.
Boosting NAD+ levels to correct redox imbalances appeared to restore metabolic stability and reduce cell death even under conditions of nutrient stress, highlighting a possible intervention pathway for delaying cartilage degeneration.
Modulating mTORC1 activity may also be a viable path for preventing or slowing the degeneration.
These findings could inform new therapies for not only mitochondrial diseases but also age-related skeletal conditions such as osteoarthritis.
However, the research remains at an early stage. The experiments were conducted in mice, and more work is needed to determine whether the same mechanisms operate in human cartilage. The long-term effects of interventions like NMN supplementation also require further study. Future research will need to strike a balance between supporting biosynthesis during growth and avoiding the risk of early tissue decline.
Reference: Bubb K, Etich J, Probst K, et al. Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging. Sci Adv. 2025;11(16):eads1842. doi: 10.1126/sciadv.ads1842
This article is a rework of a press release issued by the University of Cologne. Material has been edited for length and content.
