research HIGHLIGHTS
TECHNIQUES establishes connections between the endoplasmic reticulum (ER) and mitochondria. Confirming Many makes of mit ochondria the functional relevance of this, the cell bodies of Purkinje cells showed Mitochondria have many important Using this immunocapture more ER–mitochondrial contacts functions in the CNS, but do they technique, the authors isolated than did astrocytes or granule cell mitochondria show some functional diversity mitochondria from three different bodies. Thus, proteomic differences in neuronal across different types of neural cells? cell types in the mouse cerebellum: identified using this isolation Fecher et al. describe a method Purkinje cells (inhibitory neurons), technique can predict differences and glial cells that enables mitochondria from granule cells (excitatory neurons) and in mitochondrial function, even might be specific cell types to be captured astrocytes. Once isolated, the authors between neuronal cell types. specialized and compared. Using this method, screened the proteomes of these One potential use for this for different they reveal differences in protein mitochondria for comparison. technique might be to examine expression and function between More than 85% of the proteins disease-related changes in cell-type- functions mitochondria of different cerebellar identified were similarly abundant specific mitochondria. Fecher et al. cell types in the mouse brain. in all three cell types, suggesting labelled markers of neuronal and The authors generated MitoTag that many mitochondrial functions astrocytic mitochondria (identified mice, which show Cre-recombinase- are conserved between the cell through their proteomic analyses) in dependent expression of green types. However, almost 200 of the tissue samples from mouse models fluorescent protein (GFP) that is mitochondrial proteins identified of disease. In samples of cortex from targeted to the outer membrane were differentially regulated across APP/PS1 mice, a model of Alzheimer of mitochondria. Crossing these the three groups. A comparison disease, the number of neuronal (and, mice with mice expressing Cre of the mitochondrial proteomes of to lesser extent, glial) mitochondria under the control of a cell-type the two neuronal types with around amyloid-β plaques seemed marker generated mice with that of the astrocytes using gene to be reduced. Moreover, in spinal cell-type-specific labelling of ontology databases indicated that cords of pre-symptomatic SODG93A mitochondria. To capture cell-type- mitochondria in neuronal and mice — a model of amyotrophic specific mitochondria from a tissue glial cells might be specialized for lateral sclerosis (ALS) — neuronal, mixture of labelled and unlabelled different functions. For example, but not glial, mitochondria showed mitochondria, the authors added whereas neuronal mitochondria morphological changes compared magnetic microbeads that selectively are specialized for generating the with those in wild-type mice. bind to GFP, and applied a magnetic metabolite ubiquinone, astrocytic Notably, these mitochondrial field to separate out the GFP-labelled mitochondria seem better equipped changes were confirmed by labelling organelles. to metabolize lipids. Further cell-type-specific mitochondria experiments comparing the ability in post-mortem samples from of mitochondria to metabolize individuals with Alzheimer disease or long-chain fatty acids confirmed ALS, suggesting possible translational that astrocytic mitochondria are relevance of this approach. indeed more efficient at metabo Together, the data obtained using lizing such molecules than are the authors’ MitoTag and immuno Purkinje-cell-derived mitochondria. capture method have revealed The authors also found that mitochondrial diversity in the CNS. granule-cell-derived mitochondria Further use of this technique might expressed higher levels of the lead to a greater understanding mitochondrial calcium uniporter of why some cell types are MCU than Purkinje-cell-derived more vulnerable than others to or astrocyte-derived mitochondria. neurological diseases associated with Consistent with this finding, isolated changes in mitochondrial function. mitochondria from granule cells Natasha Bray were able to buffer calcium more Original article Fecher, C. et al. Cell-type- efficiently than mitochondria from specific profiling of brain mitochondria reveals the other two cell types. functional and molecular diversity. Nat. Neurosci. Purkinje-cell mitochondria https://doi.org/10.1038/s41593-019-0479-z (2019) Credit: Jose A. Bernat Bacete/Getty were enriched for a protein that
NatuRe Reviews | Neuroscience volume 20 | NOVEMBER 2019 | 645