Assurance of mitochondrial integrity and mammalian longevity by the p62–Keap1–Nrf2–Nqo1 cascade

Abstract

Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62 À/À mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62 À/À mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…Sqstm1 −/− mice have reduced lifespan, show premature signs of aging and increased oxidative stress, as well as increased mitochondrial damage and dysfunction, due to loss of a basal NFE2L2 antioxidant response (Kwon et al 2012). These features are recapitulated by observations in human fibroblasts and by other studies showing that chronic activation of mTORC1 with IGF-1 reduces proliferative potential and causes accumulation of damaged mitochondria and ROS, leading to cellular senescence (Bitto et al 2010b;Handayaningsih et al 2012).…”

“…Maintaining these processes could prevent aging independently of mTOR modulation. Indeed, Sqstm1 −/− mice accumulate damaged mitochondria and exhibit reduced activation of the NFE2L2 pathway and accelerated aging (Kwon et al 2012). It would be interesting to see whether Sqstm1 −/− mice or MEFs show increased markers of cellular senescence and whether clearing senescent cells in these mice would rescue the accelerated aging phenotype, as it does in the BubR1 progeroid mouse (Baker et al 2011).…”

“…p62/SQSTM1 relevance in aging and age-related pathologies p62/SQSTM1 is involved in a variety of cellular processes that are relevant for aging, including protein degradation (Pankiv et al 2007;Seibenhener et al 2004), mitophagy (Narendra et al 2010a;Geisler et al 2010a;Tang et al 2011), oxidative stress response (Jain et al 2010;Komatsu et al 2010;Lau et al 2010), metabolism regulation (Moscat and Diaz-Meco 2011), and inflammation (Lee et al 2012). The role of p62/ SQSTM1 in aging and age-related diseases is not fully understood yet, although experimental evidence suggests it is likely a critical factor: expression of p62/ SQSTM1 declines with age in mice (Kwon et al 2012), loss of p62/SQSTM1 reduces lifespan and shows several age-related effects in animal models, and reduced p62/SQSTM1 correlates with age-related pathologies in human tissues.…”

“…The p62/SQSTM1 protein is involved in several agerelated pathologies, but perhaps the most striking evidence of its importance in longevity is the premature aging phenotype of Sqstm1 −/− mice (Kwon et al 2012). Sqstm1 −/− mice have reduced lifespan, show premature signs of aging and increased oxidative stress, as well as increased mitochondrial damage and dysfunction, due to loss of a basal NFE2L2 antioxidant response (Kwon et al 2012).…”

Altering Autophagy: Mouse Models of Human Disease

“…For example, Lmna-null (lamin A-deficient) mice exhibited skeletal muscle dystrophy and cardiac hypertrophy; these pathologies were improved through rapamycin administration [34]. An oxidative environment potentially plays a crucial role in the aging process, as p62 -/-mice exhibited accelerated aging phenotypes and tissues displayed elevated oxidative stress due to defective mitochondrial electron transport [35]. Likewise, Cisd2-null mice exhibited nerve and muscle degeneration and a premature aging phenotype [36].…”