Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s Disease

Abstract

Altered brain metabolism is associated with progression of Alzheimer’s Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, “mitochondria-on-a-string” (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival.

The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration

“…Unlike dissociated neuronal culture in which the morphology of mitochondria in the soma is used to confirm neuronal health prior to imaging, explant culture does not allow access to RGC cell bodies. To circumvent this issue, we used mitochondrial membrane potential as a marker of axonal health by labeling mitochondria with tetramethylrhodamine methyl ester (TMRM), a membrane potential dependent fluorescent dye (Trushina et al, 2012; Verburg and Hollenbeck, 2008; Zhang et al, 2016). We found that Armcx1 overexpression induced a significant increase of the motile mitochondria pool compared to the PLAP control (Figure 2A and 2B and Movie S1).…”

Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin-Induced Type 1 Diabetic Rats

“…Therefore, we next determined the levels of Drp1 protein specifically in mitochondria, using a method reported in recent studies that evaluates Drp1 protein levels in the mitochondrial outer membrane by flow cytometry [28, 33]. In this assay, isolated mitochondria derived from NC and DM rats were first selected/gated according to light scattering properties (Fig.…”

“…However, as a major regulator of mitochondrial fission, Drp1 typically resides in an inactive form in the cytosol and on activation translocates to the mitochondria. In addition, experimental evidence suggests that phosphorylation of Drp1 at S616 is associated with mitochondrial elongation or fragmentation [33]. …”

Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex

“…We detected age-related morphogenetic abnormalities resulting in accumulation of mitochondria with intermingled thin (“pinched”) and enlarged segments, indicative of mitochondrial dysfunction. This phenotype has just been detected in AD brains, where it has been termed “mitochondria-on-a-string” (MOAS) (Zhang et al, 2016). Thus, the discovery of this phenotype in the aged rhesus monkey may help reveal the etiology of mitochondrial deficits in human AD.…”