Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Jul 29;4(3):e1071763.
doi: 10.1080/21624054.2015.1071763. eCollection 2015 Jul-Sep.

Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity

Konstantinos Palikaras  1 , Eirini Lionaki  2 , Nektarios Tavernarakis  3
Affiliations

Interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity

Konstantinos Palikaras et al. Worm. .

Abstract

Mitochondria are highly dynamic and semi-autonomous organelles, essential for many fundamental cellular processes, including energy production, metabolite synthesis and calcium homeostasis, among others. Alterations in mitochondrial activity not only influence individual cell function but also, through non-cell autonomous mechanisms, whole body metabolism, healthspan and lifespan. Energy homeostasis is orchestrated by the complex interplay between mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy). However, the cellular and molecular pathways that coordinate these 2 opposing processes remained obscure. In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of the mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy, and functions in the same genetic pathway with PINK-1 and PDR-1 (the nematode homologs of PINK1 and Parkin respectively) to promote longevity and prevent cell damage under stress conditions. Interestingly, accumulation of damaged mitochondria activates SKN-1 (SKiNhead-1), the nematode homolog of NRF2, which in turn initiates a compensatory retrograde signaling response that impinges on both mitochondrial biogenesis and removal. In this commentary, we discuss the implications of these new findings in the context of innate immunity and aging. Unraveling the regulatory network that governs the crosstalk between mitochondrial biogenesis and mitophagy will enhance our understanding of the molecular mechanisms that link aberrant energy metabolism to aging and disease.

Keywords: aging; autophagy; homeostasis; innate immunity; mitochondria; mitophagy; stress.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Mitochondrial quality control mechanisms. (A) Mitochondrial unfolded protein response (UPRmt) is activated under proteotoxic and metabolic stress. Misfolded and non-functional mitochondrial proteins are digested into peptides by mitochondrial proteases and are transferred to the cytoplasm through the HAF-1 transporter. In turn, ATFS-1 is activated and translocates to the nucleus to regulate transcription of nuclear genes encoding mitochondrial proteins, thus restoring and enhancing proteostasis and mitochondrial activity. (B) Mitochondrial dynamics facilitate quality control by segregating or exchanging damaged proteins and mutated mitochondrial DNA (mtDNA). (C) Severe damage triggers mitochondria-selective autophagy. Entire defective organelles are recognized, engulfed by autophagosomes and delivered to lysosomes for destruction.
Figure 2.
Figure 2.
Coordination of UPRmt, mitophagy and mitochondrial biogenesis during aging. Proteotoxic and metabolic stress impair mitochondrial homeostasis and induce ATFS-1 nuclearization. In turn, ATFS-1 orchestrates the mitochondrial unfolded protein response (UPRmt), which restores mitochondrial function. Excessive mitochondrial damage causes oxidative stress and initiates a bipartite retrograde response, mediated by SKN-1, to preserve mitochondrial homeostasis. SKN-1 coordinates expression of both mitochondrial biogenesis and mitophagy genes. Mitophagy is stimulated to eliminate entire damaged mitochondria. DCT-1, PINK-1 and PDR-1 act in the same pathway to mediate mitophagy. SKN-1 transcriptionally regulates expression of the DCT-1 mitophagy receptor. Notably, the skn-1 gene is among ATFS-1 transcriptional targets during activation of UPRmt, thus, establishing a complex interplay between UPRmt, mitophagy and mitochondrial biogenesis.
Figure 3.
Figure 3.
An intricate crosstalk between mitochondrial quality control pathways during bacterial infection. Bacterial toxins and secreted proteins impair mitochondrial function to enhance pathogen propagation. Mitochondrial damaged triggers activation of the ATFS-1, SKN-1, DAF-16 and HLH-30 transcription factors to augment mitochondrial quality control mechanisms (UPRmt, detoxification system, mitophagy and mitochondrial biogenesis) and pathogen elimination via xenophagy. This sophisticated crosstalk between mitochondrial quality control pathways upholds energy homeostasis and organismal survival during bacterial infection.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell 2012; 148:1145-59; PMID:22424226; http://dx.doi.org/10.1016/j.cell.2012.02.035 - DOI - PMC - PubMed
    1. Opalinska M, Meisinger C. Metabolic control via the mitochondrial protein import machinery. Curr Opin Cell Biol 2015; 33:42-8; PMID:25497717; http://dx.doi.org/10.1016/j.ceb.2014.11.001 - DOI - PubMed
    1. Schmidt O, Pfanner N, Meisinger C. Mitochondrial protein import: from proteomics to functional mechanisms. Nat Rev Mol Cell Biol 2010; 11:655-67; PMID:20729931; http://dx.doi.org/10.1038/nrm2959 - DOI - PubMed
    1. Andreux PA, Houtkooper RH, Auwerx J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 2013; 12:465-83; PMID:23666487; http://dx.doi.org/10.1038/nrd4023 - DOI - PMC - PubMed
    1. Palikaras K, Tavernarakis N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol 2014; 56:182-8; PMID:24486129; http://dx.doi.org/10.1016/j.exger.2014.01.021 - DOI - PubMed

LinkOut - more resources