Mitochondria modulate programmed neuritic retraction

Abstract

Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon “neuritosis.” Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability.

Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration

“…Mitochondrial isolation. Brain mitochondria were isolated by Percoll density centrifugation as described in our previous studies (27,53). Cellular mitochondria were isolated by using the mouse Mitochondria Isolation kit (Miltenyi Biotec) according to the manufacturer's protocol.…”

“…MMP decreased and ROS increased in AANAT-KO PCNs; exogenous melatonin administration restored both parameters ( Figure 2A and Supplemental Figure 2A). MMP exists as a gradient in neurons, whereby synaptic mitochondria have lower MMP than somal mitochondria, resulting in synaptic vulnerability (53). MMP is similar in somal mitochondria (<10 μm from nucleus) but decreased in synaptic AANAT-KO mitochondria (>50 μm from nucleus) (Supplemental Figure 2B).…”

Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

“…Dysfunctions in mitochondria-driven processes may causally disrupt brain circuits, affecting behavioral outputs and leading to pathological states [20]. Accumulation of damaged mitochondria in distal parts lead to neurite retraction and consequent synaptic vulnerability [155].…”

Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23

“…In R6/2 mice, mHTT-induced mitochondrial protein import inhibition occurs in presymptomatic mice and is prominently manifested in synaptic mitochondria (19). Synaptic mitochondria are more vulnerable to cellular stress than somal mitochondria, a defect exacerbated by mHTT (20). The timing of this abnormality and the direct interaction between mHTT and the TIM23 complex suggest that this is a pathophysiologically important mechanism in HD.…”