Mitochondrial Signaling and Neurodegeneration

Abstract

The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic infl ammation, and protein aggregates, remain unclear.Emerging evidence demonstrates that mitochondria are not only power-generating organelles, but also engage in signaling at multiple levels. During the bioenergetic decline associated with aging, dysfunctional mitochondria generate signals of stress (SOS) that can trigger and/or amplify neurodegenerative processes. In this chapter, we describe emerging mechanisms for mitochondrial signaling at four different levels. Mitochondria communicate (1) with each other via fusion and specialized inter-mitochondrial junctions, (2) with cytoplasmic components via posttranslational modifi cations that shift signaling pathways and promote protein aggregation, (3) with the nucleus to regulate epigenetic modifi cations and gene expression, and (4) with the systemic environment where they alter neuroendocrine and infl ammatory processes that impact neuronal function. The relevance of mitochondrial signaling to neurodegeneration is discussed.

An energetic view of stress: Focus on mitochondria

“…The systemic neuroendocrine consequences of mitochondrial defects have implications for our understanding of the pathogenic mechanism underlying mitochondrial disease onset and progression. Stress influences the biology of multiple diseases including cancer growth and metastasis (Thaker et al, 2006; Cole et al, 2015); diabetes (Faulenbach et al, 2012); neurodegenerative disorders (Schon and Przedborski, 2011; Picard and McManus, 2016), as well as cellular aging (Epel et al, 2004) and age-related physical and cognitive decline (Juster et al, 2010). Thus, combining the notions that mitochondria regulate the activation of stress responses and release of allostatic mediators, and that stress response mediators influence disease trajectory, an emerging possibility is that mitochondrial dysfunction – or mitochondrial allostatic load (MAL) – may contribute to translating stressful experiences into pathophysiological processes (Picard et al, 2014).…”

Mitochondrial Nanotunnels

“…They exchange Ca 2+ and reactive oxygen species (ROS) with the endoplasmic reticulum (ER) as well as with each other [ 4 – 6 ], and also communicate with the nucleus where they may regulate the transcription of important nuclear genes [ 7 ] via the release of metabolic intermediates and proteins acting as transcriptional regulators [ 8 – 10 ]. As a result, mitochondria impact on complex cellular processes including differentiation, stemness, and oncogenic behavior, and ultimately influence concerted physiological states that also contribute to aging and neurodegenerative disease [ 11 , 12 ].…”

The rise of mitochondria in medicine

“…Potential mechanisms involve the production of abnormal mitochondrial signals that may contribute intracellularly to cytoplasmic protein aggregates, epigenetic anomalies and gene expression dysregulation in the cell nucleus, as well as systemic neuroendocrine and metabolic effects that feedback on the brain (Picard and McManus, 2016). Notably, mitochondria-targeted antioxidant treatment has successfully prevented early pathological changes in preclinical studies of Alzheimers’ disease (McManus et al, 2011), suggesting that abnormal mitochondrial shape and function may precede and directly contribute to neurodegenerative processes, rather than being a secondary consequence.…”