Elsevier

Experimental Gerontology

Volume 56, August 2014, Pages 182-188
Experimental Gerontology

Review
Mitochondrial homeostasis: The interplay between mitophagy and mitochondrial biogenesis

https://doi.org/10.1016/j.exger.2014.01.021Get rights and content

Highlights

  • Mitochondrial quality control mechanisms preserve cellular homeostasis.

  • Mitochondrial dysfunction triggers mitochondrial biogenesis and mitophagy.

  • PINK1/Parkin and BNIP3/BNIP3L regulate mitophagy.

  • PGC-1α is the core regulator of mitochondrial biogenesis.

  • Mitochondrial biogenesis and mitophagy are tightly coupled processes.

Abstract

Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing.

Introduction

Mitochondria are double membrane-bound organelles, essential for energy production and cellular homeostasis in eukaryotic cells. Additionally, mitochondria have vital roles in calcium signaling and storage, metabolite synthesis and apoptosis. The strict regulation of mitochondrial mass, distribution and activity is a key aspect of maintenance of cellular homeostasis. The role of mitochondria in animal physiology is extensively investigated and suggests a direct link between mitochondrial metabolism and the process of ageing. Mitochondrial dysfunction is now considered as a major hallmark of ageing, highlighting the significance of proper mitochondrial activity for survival (Lopez-Otin et al., 2013).

Mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy) regulate cellular adaptation in response to mitochondrial malfunction. Thus, mitochondrial biogenesis and elimination of damaged and superfluous mitochondria are highly regulated processes and influence both mitochondrial and cellular homeostasis. The significance of coordination between these processes is underlined by evidence indicating that increased mitochondrial content is a common denominator of several pathologic conditions (Malpass, 2013, Vafai and Mootha, 2012). Similar progressive mitochondrial accumulation is observed during ageing in multiple cell types of diverse organisms ranging from yeast to mammals (Artal-Sanz and Tavernarakis, 2009, Bereiter-Hahn et al., 2008, Kaeberlein, 2010, Lee et al., 2002a, Lee et al., 2002b, Preston et al., 2008). However, the molecular mechanisms that contribute to aberrant increase in mitochondrial mass and disruption of mitochondrial homeostasis remain largely elusive. Here we survey the molecular pathways that govern mitochondrial biogenesis and mitochondrial turnover, and discuss how decoupling of these processes impinges on ageing and age-related diseases.

Section snippets

Molecular pathways regulating mitochondrial biogenesis

Mitochondria are semi-autonomous organelles, possessing their own circular genome. mtDNA encodes 13 proteins with essential function in respiratory complexes, 22 tRNAs and two rRNAs (Calvo and Mootha, 2010). The majority of mitochondrial proteins are encoded by nuclear genes, synthesized within the cytosol and then imported into mitochondria. Mitochondrial biogenesis is a sophisticated and multistep process, including mtDNA transcription and translation, translation of nucleus-derived

Mitochondrial quality control and homeostasis

Alongside their essential metabolic function, mitochondria are also a major source of reactive oxygen species (ROS). Eukaryotes have evolved several quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage. Mitochondria contain their own proteolytic system to monitor and degrade misfolded or unfolded proteins inside mitochondrial compartments (Fig. 1A) (Baker and Haynes, 2011, Matsushima and Kaguni, 2012). Furthermore, the proteasome system is involved in the

Co-regulation of mitochondrial biogenesis and mitophagy

The coordination between two opposing processes such as mitochondrial biogenesis and mitophagy fine tunes the quantity and quality of mitochondrial population and allows cells to adjust their mitochondrial content in response to cellular metabolic state, stress and other intracellular or environmental signals. Imbalanced response to either of two processes results in functional deterioration of biological systems and promotes cell death. During ageing and in several pathologic conditions a

Concluding remarks

Mitophagy and mitochondrial biogenesis are tightly coupled. A balanced interplay between these two processes is prerequisite for cellular adaptation and stress resistance. Recent findings hint that imbalance between the two results in cellular degeneration and stimulation of cell death pathways. Although the role of mitochondria-selective autophagy is crucial in many physiological and pathological conditions, the molecular mechanisms regulating mitophagy during ageing are not well defined.

Conflict of interest

The authors have no conflicts of interests.

Acknowledgments

We apologize to those colleagues whose work could not be referenced directly owing to space limitations. Work in the authors' laboratory is also funded by grants from the Greek General Secretariat for Research and Technology, the European Research Council (ERC) and the European Commission 7th Framework Programme.

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