Erkkinen, M. G., Kim, M.-O. & Geschwind, M. D. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 10, a033118 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Lane, N. & Martin, W. The energetics of genome complexity. Nature 467, 929–934 (2010).

Article  PubMed  CAS  Google Scholar 

Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

Article  PubMed  CAS  Google Scholar 

Scheibye-Knudsen, M. et al. Protecting the mitochondrial powerhouse. Trends Cell Biol. 25, 158–170 (2015).

Article  PubMed  CAS  Google Scholar 

Misgeld, T. & Schwarz, T. L. Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron 96, 651–666 (2017).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Exner, N. et al. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 3038–3062 (2012).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Cheng, X. T., Huang, N. & Sheng, Z. H. Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron 110, 1899–1923 (2022).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat. Rev. Mol. Cell Biol. 19, 109–120 (2018).

Article  PubMed  CAS  Google Scholar 

Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

Article  PubMed  CAS  Google Scholar 

Burte, F. et al. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat. Rev. Neurol. 11, 11–24 (2015).

Article  PubMed  CAS  Google Scholar 

Wilson, D. M. et al. Hallmarks of neurodegenerative diseases. Cell 186, 693–714 (2023).

Article  PubMed  CAS  Google Scholar 

Henrich, M. T. et al. Mitochondrial dysfunction in Parkinson’s disease—a key disease hallmark with therapeutic potential. Mol. Neurodegen. 18, 83 (2023).

Article  Google Scholar 

Elkouzi, A. et al. Emerging therapies in Parkinson disease—repurposed drugs and new approaches. Nat. Rev. Neurol. 15, 204–223 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Prasuhn, J., Davis, R. L. & Kumar, K. R. Targeting mitochondrial impairment in Parkinson’s disease: challenges and opportunities. Front. Cell Dev. Biol. 8, 615461 (2020).

Article  PubMed  Google Scholar 

Singh, A., Faccenda, D. & Campanella, M. Pharmacological advances in mitochondrial therapy. eBioMedicine 65, 103244 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Svensson, J. E. et al. Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol. BMC Neurol. 24, 111 (2024).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zheng, W. et al. Mitophagy activation by rapamycin enhances mitochondrial function and cognition in 5×FAD mice. Behav. Brain Res. 463, 114889 (2024).

Article  PubMed  CAS  Google Scholar 

Lautrup, S. et al. NAD+ in brain aging and neurodegenerative disorders. Cell Metab. 30, 630–655 (2019).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Berven, H. et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat. Commun. 14, 7793 (2023).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Narendra, D. et al. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Okatsu, K. et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat. Commun. 3, 1016 (2012).

Article  PubMed  Google Scholar 

Okatsu, K. et al. A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J. Biol. Chem. 288, 36372–36384 (2013).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Pickrell, A. M. & Youle, R. J. The roles of PINK1, Parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Heo, J. M. et al. The PINK1–PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Yamano, K. & Youle, R. J. PINK1 is degraded through the N-end rule pathway. Autophagy 9, 1758–1769 (2013).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Liu, Y. et al. The ubiquitination of PINK1 is restricted to its mature 52-kDa form. Cell Rep. 20, 30–39 (2017).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Gladkova, C. et al. Mechanism of Parkin activation by PINK1. Nature 559, 410–414 (2018).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Allen, G. F., Toth, R., James, J. & Ganley, I. G. Loss of iron triggers PINK1/parkin-independent mitophagy. EMBO Rep. 14, 1127–1135 (2013).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Michaelis, J. B. et al. Protein import motor complex reacts to mitochondrial misfolding by reducing protein import and activating mitophagy. Nat. Commun. 13, 5164 (2022).

Article