Mitonuclear protein imbalance as a conserved longevity mechanism

By R. Houtkooper, L. Mouchiroud, D. Ryu, N. Moullan, E. Katsyuba, G. Knott, Robert W. Williams, Johan Auwerx. Nature, 2013

994 citations recorded by the source corpus.

Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.

Subfields: Aging, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a7ceb1e8829d035fa2dce969ea6418b1c317275b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. L. Guarente
2. D. Sinclair
3. Johan Auwerx
4. C. Cantó
5. Toren Finkel
6. S. Imai
7. R. Houtkooper
8. Keir J. Menzies

In Molecular Biology

1. L. Guarente
2. D. Sinclair
3. Johan Auwerx
4. R. Houtkooper
5. C. Cantó
6. Toren Finkel
7. S. Imai
8. D. Finley

Citations in the corpus

• Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals (2017, methodology): “Surprisingly, under the conditions used, we did not detect activation of the prototypical UPRmt, which is generally characterized by the induction of the chaperones HSP60 and HSP10 and the protease CLPP, among others, and which has been mainly described in invertebrates and cellular models as the pr”
• NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “Likewise, the activation of the UPRmt by targeting mitochondrial ribosomal protein (Mrp) translation, using a knockdown of ribosomal proteins or antibiotics that specifically inhibitmitochondrial translation, increases longevity inC. elegans (Houtkooper et al., 2013).”
• Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice (2016, positive): “Additionally, NMN-treated skeletal muscle showed enhanced mitonuclear protein imbalance (Houtkooper et al., 2013; Mouchiroud et al., 2013), which has recently been reported to correlate to enhanced NAD+ biosynthesis andmitochondrial oxidative metabolism in human skeletal muscle (van de Weijer et…”
• The Mitochondrial Basis of Aging (2016, background): “Another apparent way in which the UPRmt appears to be activated is when there is a stoichiometric imbalance between mitochondrial and nuclear proteins (Houtkooper et al., 2013).”
• The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling (2013, positive): “Alternatively, disturbance of the delicate balance between mitochondrial protein production from nDNA and mtDNA—a state we termed mitonuclear protein imbalance—is associated with UPRmt activation (Houtkooper et al., 2013).”
• Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling (2018, neutral): “…to be necessary for the longevity phenotypes include the intrinsic apoptosis signaling pathway, which is stimulated by ROS, and the mitochondrial unfolded protein response, which is required for the survival of worms with damaged mitochondria (Houtkooper et al., 2013; Yee et al., 2014).”
• Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “HIF-1a modulation may have differential effects on lifespan depending on the animal’s diet or whether the mtUPR is activated (Dillin et al., 2002; Durieux et al., 2011; Houtkooper et al., 2013).”