Linking Lysosomal Biomarkers and Ecotoxicological Effects at Higher Biological Levels - Ecological Biomarkers: Indicators of Ecotoxicological Effects - page 116

Although the genes for autophagy were initially discovered in yeast, analogues of those
genes are now being found in diverse groups of animals including nematode worms,
fruit flies, and mammals (Cuervo 2004). In this chapter, we have considered the role of
lysosomal autophagy as a protective system against the consequences of oxidative stress,
and will subsequently discuss its significance in the development of tolerance in aquatic
ecosystems.
Pollutant exposure often causes oxidative attack on the protein machinery and organelles
of the cell (Livingstone 2001; Figure 5.1). An effective ability to up-regulate the autophagic
process will obviously be advantageous to organisms exposed to pollutants, since this will
facilitate the removal of damaged cellular constituents, conserve cell function (Figure 5.4;
Kirchin et al. 1992; Cuervo 2004; Lockshin and Zakeri 2004), and reduce the amount of age
pigment (lipofuscin) produced (Figure 5.4; Grune et al. 2004). Lipofuscin accumulates in
lysosomes as a result of peroxidation of autophagocytosed proteins associated with pro-
tein aggregates and oxidatively damaged organelles (Figure 5.4), and was previously con-
sidered to be just cellular junk (Grune et al. 2004). However, new evidence indicates that
lipofuscin binds iron, which generates ROS, resulting in exacerbation of oxidative damage
(Brunk and Terman 2002; Dailianis et al. 2003). Brunk and Terman (2002) also hypothesize
that lipofuscin binds lysosomal hydrolases, thereby inhibiting protein degradation. The
outcome is failed autophagy with autophagic accumulation of essentially undegradable

Oxidative stress and autophagy

Reactive oxygen
species

Reactive oxygen
species

Proteins

Autophagy

Oxidatively
damaged
proteins

Organelles, e.g.,
mitochondria

Autophagy

Autophagy

Protein
breakdown

Autophagy

Injured
organelles

Accumulation of
lipofuscin -
generate more ROS
and may inhibit
proteolysis

Autophagy

Protein
aggregates-
aggresomes?

Lysosomal
compartment

Cell injury and
death

Amino acids

FIGURE 5.4
Conceptual mechanistic model for effects of autophagy and ROS on proteins and cellular organelles. The
model shows normal autophagic turnover of proteins and organelles (arrows) with superimposed augmented
autophagy (large arrows), which is postulated as having a protective role against oxidative stress. If augmented
autophagy of damaged organelles and proteins is impaired, as occurs in cells with lysosomal damage and
autophagic degradative dysfunction, then harmful products can accumulate contributing to cell injury (see
Moore et al. 2006a, 2006b, 2007). (Modified from Moore, M.N. et al., Aquat. Toxicol. , 84:80-91, 2007.)