Abstract
Disrupting particular mitochondrial fission and fusion proteins leads to the death of specific neuronal populations; however, the normal functions of mitochondrial fission in neurons are poorly understood, especially in vivo, which limits the understanding of mitochondrial changes in disease. Altered activity of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) may contribute to the pathophysiology of several neurologic diseases. To study Drp1 in a neuronal population affected by Alzheimer's disease (AD), stroke, and seizure disorders, we postnatally deleted Drp1 from CA1 and other forebrain neurons in mice (CamKII-Cre, Drp1lox/lox (Drp1cKO)). Although most CA1 neurons survived for more than 1 year, their synaptic transmission was impaired, and Drp1cKO mice had impaired memory. In Drp1cKO cell bodies, we observed marked mitochondrial swelling but no change in the number of mitochondria in individual synaptic terminals. Using ATP FRET sensors, we found that cultured neurons lacking Drp1 (Drp1KO) could not maintain normal levels of mitochondrial-derived ATP when energy consumption was increased by neural activity. These deficits occurred specifically at the nerve terminal, but not the cell body, and were sufficient to impair synaptic vesicle cycling. Although Drp1KO increased the distance between axonal mitochondria, mitochondrial-derived ATP still decreased similarly in Drp1KO boutons with and without mitochondria. This indicates that mitochondrial-derived ATP is rapidly dispersed in Drp1KO axons, and that the deficits in axonal bioenergetics and function are not caused by regional energy gradients. Instead, loss of Drp1 compromises the intrinsic bioenergetic function of axonal mitochondria, thus revealing a mechanism by which disrupting mitochondrial dynamics can cause dysfunction of axons.
Highlights
There are several potential reasons why specific neurons have unique requirements for fission–fusion proteins
We showed that most midbrain DA neurons are uniquely vulnerable to loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1),[4] a GTPase recruited to fission sites on the outer mitochondrial membrane.[1]
Received 10.11.14; revised 15.2.15; accepted 02.3.15; Edited by A Verkhratsky between neurons? Notably, Drp[1] may have mitochondria-independent functions in synaptic vesicle release.[8]. Addressing these issues could help elucidate the physiological functions of mitochondrial dynamics in the nervous system and reveal how shifts in the fission–fusion balance contribute to selective neuronal death in neurodegenerative diseases, including Huntington’s disease, Parkinson’s disease and Alzheimer’s disease (AD),[1,4] and in other neurologic disorders, including stroke and epilepsy.[9,10,11]
Summary
There are several potential reasons why specific neurons have unique requirements for fission–fusion proteins. A subpopulation of midbrain DA neurons survive, despite losing their axonal mitochondria, suggesting that they have lower needs for energy or other mitochondrial functions in their axons.[4] Do unique requirements for mitochondrial dynamics underlie differential neuronal vulnerability? Drp[1] loss markedly decreased the number of mitochondria in axons and the cell body in midbrain DA neurons in vivo,[4] and reduced staining of complex I and IV activity in cerebellar neurons in vivo.[14] it is unclear whether these changes translate into decreased ATP levels in neurons and, if so, whether this decrease compromises neuronal function. We found that Drp[1] is required to maintain normal mitochondrial-derived ATP levels in axons (but not the cell body), and that the loss of this function is unrelated to the distribution of mitochondria within axons
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