Mitochondrial deficiency: a double-edged sword for aging and neurodegeneration

Abstract

For decades, aging was considered the inevitable result of the accumulation of damaged macromolecules due to environmental factors and intrinsic processes. Our current knowledge clearly supports that aging is a complex biological process influenced by multiple evolutionary conserved molecular pathways. With the advanced age, loss of cellular homeostasis severely affects the structure and function of various tissues, especially those highly sensitive to stressful conditions like the central nervous system. In this regard, the age-related regression of neural circuits and the consequent poor neuronal plasticity have been associated with metabolic dysfunctions, in which the decline of mitochondrial activity significantly contributes. Interestingly, while mitochondrial lesions promote the onset of degenerative disorders, mild mitochondrial manipulations delay some of the age-related phenotypes and, more importantly, increase the lifespan of organisms ranging from invertebrates to mammals. Here, we survey the insulin/IGF-1 and the TOR signaling pathways and review how these two important longevity determinants regulate mitochondrial activity. Furthermore, we discuss the contribution of slight mitochondrial dysfunction in the engagement of pro-longevity processes and the opposite role of strong mitochondrial dysfunction in neurodegeneration.

Neuronal Genes and Developmental Neuronal Pathways in Drosophila Life Span Control

“…Serine-threonine protein kinase Glycogen syntase kinase 3 beta (GSK3-beta) encoded by the gene sgg ( (2011), Troulinaki and Bano (2012). Genes (proteins) involved in life span control are in red (for references, see Inoki and Guan 2006).…”

Neuronal Inputs and Outputs of Aging and Longevity

“…Intriguingly, protein misfolding, whether it is mediated (Morley et al, 2002;van Ham et al, 2010) or not (David et al, 2010) by polyglutamine repeats, increases with age. This suggests that protein aggregation is inherent with age and is not restricted to a subset of proteins that have been implicated in diseases like neurodegeneration (David et al, 2010).…”

“…Similarly, mitochondrial dysfunction has been implicated in neurodegenerative diseases (reviewed in Eckert et al, 2011;Reddy and Reddy, 2011;Swerdlow, 2011;Troulinaki and Bano, 2012;Yin et al, 2012), although it remains unclear whether the functional changes seen in the healthily aging brain are distinct Frontiers in Genetics | Genetics of Aging from the pathological processes associated with neurodegenerative diseases. The empirical evidence at hand today thus suggests that neuronal mitochondria play an important role in maintaining organismal homeostasis and in influencing aging.…”

“…Not surprisingly, mitochondrial activity is also regulated by major pathways that affect longevity, including the IIS, TOR, and JNK signaling pathways (reviewed in Troulinaki and Bano, 2012, as part of this Research Topic). Indeed, the ROS-mediated induction of JNK activity (Wang et al, 2005), which leads to translocation of JNK from the cytoplasm to the mitochondria, has been proposed to be of fundamental importance in the transduction of cytosolic signals to the mitochondria in the aging mammalian brain Schroeter et al, 2003;Eminel et al, 2004;Zhou et al, 2008Zhou et al, , 2009.…”

Genetic variation in neurodegenerative diseases and its accessibility in the model organism Caenorhabditis elegans

“…TORC1 signaling transactivates/represses PH4-4 that induces pro-survival factors expression for life extension under nutrient restriction [85]. Moreover, TORC1 can increase protein synthesis and extends lifespan by both activating the ribosomal subunit S6 kinase (S6K) and inhibiting 4E-BP1 (a negative regulator of translation) [81, 97]. Meanwhile, investigations in C. elegans as well as other organisms have shown that autophagy is induced by inhibition of TORC1 [46].…”