Minireview
Selective degradation of mitochondria by mitophagy

https://doi.org/10.1016/j.abb.2007.03.034Get rights and content

Abstract

Mitochondria are the essential site of aerobic energy production in eukaryotic cells. Reactive oxygen species (ROS) are an inevitable by-product of mitochondrial metabolism and can cause mitochondrial DNA mutations and dysfunction. Mitochondrial damage can also be the consequence of disease processes. Therefore, maintaining a healthy population of mitochondria is essential to the well-being of cells. Autophagic delivery to lysosomes is the major degradative pathway in mitochondrial turnover, and we use the term mitophagy to refer to mitochondrial degradation by autophagy. Although long assumed to be a random process, increasing evidence indicates that mitophagy is a selective process. This review provides an overview of the process of mitophagy, the possible role of the mitochondrial permeability transition in mitophagy and the importance of mitophagy in turnover of dysfunctional mitochondria.

Section snippets

General features of autophagy

Autophagy is the process by which organelles and bits of cytoplasm are sequestered and subsequently delivered to lysosomes for hydrolytic digestion [9]. Autophagy is ongoing in nucleated cells and is typically activated by fasting and nutrient deprivation. In the liver particularly, glucagon promotes autophagy, whereas insulin negatively regulates it [10], [11]. During fasting, autophagy is important for generating amino acids, fueling the tricarboxylic cycle, and maintaining ATP energy

Molecular control of autophagy

Phosphoinositide 3-kinases (PI3Ks) phosphorylate phosphatidylinositol at position 3 of the inositol ring and play an important role in the regulation of autophagy [22]. PI3K inhibitors, such as 3-methyladenine, wortmannin, and LY294002, potently block autophagy. However, different classes of PI3K exert opposing effects on autophagy: Class III PI3K promotes sequestration of autophagic vacuoles, whereas class I PI3K inhibits autophagy. Class III PI3K/p150 associates with Beclin1, a mammalian

Selective autophagy

Whether autophagy is selective or non-selective has been controversial. Cytosolic enzymes with different half-lifes are sequestered at similar rates during autophagy, and autophagosomes often contain a variety of different cytoplasmic elements, including cytosolic proteins and organelles such as ER, peroxisomes and mitochondria [30], [31]. Such findings led to the assumption that autophagy is a non-specific form of lysosomal degradation. However, more recent findings indicate that autophagy can

Characteristics and possible structure of mitochondrial permeability transition pores

Recent evidence suggests a possible involvement of the MPT in autophagy. In the MPT, opening of PT pores causes mitochondria to become permeable to all solutes up to a molecular mass of about 1500 Da, an event leading to mitochondrial depolarization and activation of the mitochondrial ATPase (ATP synthase operating in reverse) [38], [39], [40], [41]. After the MPT, mitochondria undergo large amplitude swelling driven by colloid osmotic forces, which culminates in rupture of the outer membrane

Mitophagy induced by nutrient deprivation

A role of the MPT in mitophagy is implicated in cultured hepatocytes during nutrient deprivation. Autophagic stimulation of rat hepatocytes by serum deprivation and glucagon (a hormone released to the liver during fasting) increases the rate of spontaneous depolarization of mitochondria by 5-fold to about 1% of mitochondria per hour (Fig. 3) [53]. These depolarized mitochondria move into acidic vacuoles, which also increase in number after nutrient deprivation. The acidic structures containing

Mitophagy after photodamage

Autophagic processes have long been proposed to remove damaged and dysfunctional mitochondria. Direct experimental confirmation of a role of autophagy in removing damaged mitochondria comes in experiments in which selected mitochondria inside living hepatocytes are subjected to laser-induced photodamage [56]. When portions of GFP–LC3-expressing hepatocyes cells containing 5–10 mitochondria are exposed to a pulse of 488-nm light from an argon laser, mitochondrial depolarization occurs in a light

Mitophagy and cell death

Controversy exists as to whether autophagy promotes or prevents cell death [12], [59], [60]. If autophagy removes damaged mitochondria that would otherwise activate caspases and apoptosis, then autophagy should be protective. In agreement, disruption of autophagic processing and/or lysosomal function promotes caspase-dependent cell death [60], [61]. However, excessive and dysregulated autophagy may promote cell death, since enzymes leaking from lysosomes/autolysosomes, such as cathepsins and

Mitophagy in aging

Aging seems to affect mitochondria particularly. Because of mitochondrial ROS generation, protein damage occurs in mitochondria, and mutations of mtDNA accumulate. mtDNA is more susceptible to oxidative damage than nuclear DNA since histones are not present in mitochondria to protect mtDNA and because DNA repair mechanisms in mitochondria are less robust than in the nucleus [8], [64]. Moreover, virtually all mtDNA is transcriptionally active compared to 2% or 3% of nuclear DNA, which also makes

Conclusion

In normal physiology, cells utilize autophagy to rid themselves of damaged, dysfunctional, and superfluous cytoplasmic components to maintain cellular homeostasis and adjust to changing physiological demands. In this respect, mitochondrial degradation by autophagy (mitophagy) may play an essential role in maintaining mitochondrial functional and genetic integrity. However, there is a need for a better understanding of the regulatory pathways that control mitophagy and the specific signals and

References (75)

  • J.J. Lemasters et al.

    Biochim. Biophys. Acta

    (1998)
  • J.S. Kim et al.

    Gastroenterology

    (2003)
  • B. Levine et al.

    Dev. Cell

    (2004)
  • F. Reggiori

    Curr. Top. Dev. Biol.

    (2006)
  • Y. Ohsumi et al.

    Semin. Cell Dev. Biol.

    (2004)
  • M. Matsushita et al.

    J. Biol. Chem.

    (2007)
  • I. Tanida et al.

    Int. J. Biochem. Cell Biol.

    (2004)
  • A.J. Meijer et al.

    Mol. Aspects Med.

    (2006)
  • T. Noda et al.

    J. Biol. Chem.

    (1998)
  • A.R. Bellu et al.

    J. Biol. Chem.

    (2001)
  • O.B. Kotoulas et al.

    Pathol. Res. Pract.

    (2006)
  • I. Kissova et al.

    J. Biol. Chem.

    (2004)
  • D.R. Hunter et al.

    J. Biol. Chem.

    (1976)
  • M. Zoratti et al.

    Biochim. Biophys. Acta

    (1995)
  • G. Beutner et al.

    FEBS Lett.

    (1996)
  • E. Basso et al.

    J. Biol. Chem.

    (2005)
  • L. He et al.

    FEBS Lett.

    (2002)
  • L. He et al.

    J. Biol. Chem.

    (2003)
  • L. He et al.

    Biochem. Biophys. Res. Commun.

    (2005)
  • D.R. Pfeiffer et al.

    J. Biol. Chem.

    (1995)
  • M. Lam et al.

    J. Biol. Chem.

    (2001)
  • D.B. Zorov et al.

    Biochim. Biophys. Acta

    (2006)
  • V.A. Bohr

    Free Radic. Biol. Med.

    (2002)
  • R.A. Menzies et al.

    J. Biol. Chem.

    (1971)
  • E. Bergamini

    Mol. Aspects Med.

    (2006)
  • N. Camougrand et al.

    FEMS Yeast Res.

    (2004)
  • B.K. Kennedy et al.

    Trends Genet.

    (1996)
  • B.K. Kennedy et al.

    Cell

    (1995)
  • E. Bergamini et al.

    Biomed. Pharmacother.

    (2003)
  • M. Saraste

    Science

    (1999)
  • B. Chance et al.

    Physiol. Rev.

    (1979)
  • J.F. Turrens et al.

    Arch. Biochem. Biophys.

    (1985)
  • G.J. Gores et al.

    Am. J. Physiol.

    (1989)
  • T.L. Dawson et al.

    Am. J. Physiol.

    (1993)
  • F.M. Yakes et al.

    Proc. Natl. Acad. Sci. USA

    (1997)
  • A.U. Arstila et al.

    Am. J. Pathol.

    (1968)
  • C.M. Schworer et al.

    Proc. Natl. Acad. Sci. USA

    (1979)
  • Cited by (1329)

    View all citing articles on Scopus

    This work was supported, in part, by Grants 2-R01 DK37034, 1 P01 DK59340 and C06 RR015455 from the National Institutes of Health.

    View full text