Mitophagy in Aging Brains

The brain uses a great deal of energy, and thus, mitochondria are critical to brain health. Damaged or worn-out mitochondria are removed by mitophagy, and impaired mitophagy has been associated with Alzheimer’s and Parkinson’s diseases. The laboratory of Thomas McWilliams at the University of Helsinki showed that mitophagy levels increased differently in different areas of aging mouse brains. They increased in areas responsible for movement, but decreased in those for memory. These results provide insights that may be valuable for healthy brain aging.

Rappe A, Vihinen HA, Suomi F, Hassinen AJ, Ehsan H, Jokitalo ES, McWilliams TG (2024) Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging. The EMBO Journal 43(23): 6199-6231.

 

Impaired Mitochondria Affect Skeletal Aging

Patients with impaired mitochondrial respiratory chain capacity often have show reduced levels of skeletal growth that are similar to premature degeneration of cartilage and aging. A research team led by Bent Brachvogel at the University of Cologne in Germany examined cartilage cells in mice with impaired cellular respiration. They found that those cells tended to lose the ability to regenerate and died to accelerate aging. In this way, they identified basic processes that might be therapeutic targets.

Bubb K, Etich J, Probst K, Parashar T, Schuetter M, Dethloff F, Reincke S, Nolte JL, Krüger M, Schlötzer-Schrehard U, Nüchel J (2025) Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging. Science Advances 11(16): eads1842.

 

Balancing Mitochondrial Transcription and Replication

The small mitochondrial genome serves as a template for replicating the DNA genome and for transcribing RNAs that encode proteins. The balance between these two functions is critical for mitochondrial health. However, the mechanism for this balancing is unknown. Recently, a team led by Takehiro Yasukawa at Kyushu University in Japan studied the role of mitochondrial transcription elongation factor (TEFM) in the process. They report that knockout of the TEFM gene resulted in reduced ability to make the transition from transcription to replication. This study provides additional insights into the biology of mitochondria.

Matsuda S, Nakayama M, Do Y, Ishiuchi T, Yagi M, Wanrooij S, Nakada K, Wei FY, Ichiyanagi K, Sasaki H, Kang D (2025) TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA. Communications Biology 8(1): 202.

 

Mitochondria at the Synapse

Mitochondria are important in synaptic transmission and plasticity, but how they do this is unknown. Sannon Farris and her team at Virginia Technical University looked at the mitochondrial calcium uniporter (MCU) that couples neuronal activity to ATP production. There is more MCU in hippocampal CA2 distal than proximal dendrites, and distal dendrites have more plasticity. However, the mechanism is unknown.  Mice with a CA2-specific MCU knockout had fragmented mitochondria that might explain their functional deficits a synapses. These differences in MCU expression might be the mechanism used by different cell types to modulate mitochondrial function to different needs.

Pannoni KE, Fischer QS, Tarannum R, Cawley ML, Alsalman MM, Acosta N, Ezigbo C, Gil DV, Campbell LA, Farris S (2025) MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity. Scientific Reports 15(1): 4540.

 

Recycling Mitochondria

Cells with damaged mitochondrial DNA have been implicated in numerous diseases and aging. A team led by David Pla-Martín at Heinrich-Heine University Düsseldorf in Germany discovered a mechanism that deals with those mitochondria with damaged DNA. That mechanism depends on a protein complex called the retromer and lysosomes, which contain digestive enzymes. Together they recycle the mitochondrial components and eliminate the damaged mitochondria. The authors speculate that dysfunction in this recycling mechanism might be involved in disease pathogenesis.

Kakanj P, Bonse M, Kshirsagar A, Gökmen A, Gaedke F, Sen A, Mollá B, Vogelsang E, Schauss A, Wodarz A, Pla-Martín D (2025) Retromer promotes the lysosomal turnover of mtDNA. Science Advances 11(14): eadr6415.

 

How Mitochondria Produce Energy

Mitochondria have long been known to be the organelle that produces energy from sugar in the food we eat. However, the precise machinery that accomplishes this activity is unknown. Now, using cryo-electron microscopy, a team from the laboratory of Edmund Kunji at the MRC Mitochondrial Biology Unit, Cambridge determined the atomic structure of the mitochondrial pyruvate carrier that transports the key molecule pyruvate. This mechanism allows pyruvate to cross the normally impermeable inner mitochondrial membrane. Understanding this machine will allow scientists to develop drugs that interact with it and serve as therapies for a variety of diseases.

Sichrovsky M, Lacabanne D, Ruprecht JJ, Rana JJ, Stanik K, Dionysopoulou M, Sowton AP, King MS, Jones SA, Cooper L, Hardwick SW. (2025) Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. Science Advances 11(16): eadw1489.