Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function And Calcium Signaling Part 4

MAMs are often found at synapses, where they may modulate synaptic activity [213]. Efficient ER-to-mitochondria Ca2+ transfer is necessary for ATP production and may be especially important for meeting the high energetic demands of synaptic transmission [214] and/ or serve as an important mechanism to buffer synaptic Ca2+.

Human memory is very important, which can help us learn new knowledge, master skills, and recall good experiences in the past. Synaptic activity also plays a very important role in the development and maintenance of memory.

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The ER and mitochondrial membranes are held in apposition at MAMs via a network of tether proteins [215, 216], some of which have been implicated in NDDs. ER-mitochondrial tethers include the ER-mitochondria encounter structure (ERMES), which was identified in yeast [217].

Mammalian counterparts to the ERMES complex are still being validated but may include the IP3 receptor, phosphoric acidic cluster sorting protein-2 (PACS-2), B-cell receptor-associated protein 31 (Bap31), PDZD8 in the ER, the mitochondrial fission protein Fis1, and the outer mitochondrial membrane protein VDAC [218].

PDZD8 is required for ER-mitochondria tethering, and loss of PDZD8 is sufficient to impact ER-mitochondrial Ca2+ dynamics in mammalian neurons [219]. Mitofusin 2 has also been proposed as a MAM tether [220], but this idea remains controversial [221, 222].

Additional proposed tethers include the oxysterol binding-related proteins ORP5 and ORP8, which can interact with mitochondrial protein tyrosine phosphatase interacting protein 51 (PTPIP51) [223].

The OMM protein synaptojanin 2 binding protein (SYNJ2BP) and the ER protein ribosome-binding protein 1 (RRBP1) are proposed to mediate specific interactions between the rough ER and mitochondria [224].

Finally, a tethering complex that may have particular importance in NDDs is comprised of the ER vesicle-associated membrane proteins-associated protein B (VAPB) and mitochondrial PTPIP51 [225, 226].

Altered ER-mitochondrial contacts in NDDs may contribute to disease pathology [227, 228]. Loss of MAM tethers can disrupt ER-mitochondrial Ca2+ transfer and so impair mitochondrial metabolism, leading to cellular energy depletion and the activation of autophagy [229, 230].

MAM disruption in NDDs could also lead to energetic compromise by impairing the synthesis of phospholipids important for mitochondrial membranes, such as cardiolipin [208, 231, 232].

This species is enriched in the mitochondrial inner membrane and is critical for proper ETC and ATP synthase function [233–236]. Finally, mitochondrial associations regulate several processes that are commonly disrupted in NDDs such as Ca2+ handling, inflammation, axonal transport, and mitochondrial function [237].

These observations support the hypothesis that altered ER-mitochondrial communication is a common mechanism underlying NDDs. The AD-related proteins APP and γ-secretase are all enriched at MAMs [238]. Observations of altered lipid metabolism and Ca2+ handling in both FAD and SAD suggest that these proteins may be associated with MAM dysfunction [228, 239].

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Altered i Ca2+ handling in AD could result from enhanced ER-mitochondrial Ca2+ transfer. The funding that ER Ca2+ concentration is increased in AD supports this view.

Finally, altered lipid homeostasis resulting from dysfunctional ER/mitochondrial tethering may also impair mitochondrial energetics in AD. The MAMs of AD brain tissue and cells exhibit increased sphingomyelin hydrolysis by sphingomyelinase, which leads to increased ceramide content [240].

Increased ceramide content in AD appears sufficient to impair mitochondrial respiration [241, 242], as pharmacologic reduction of ceramide levels in AD models can rescue mitochondrial respiration [240].

Specific mechanisms by which elevated ceramide content in mitochondrial membranes may impair respiratory function and cellular bioenergetics have been detailed elsewhere [173].

Furthermore, altered ER-mitochondrial contacts and signaling are reported in PD, leading some to propose that disrupted MAMs are a significant contributor to PD pathogenesis [228, 237].

Proteins that are implicated in familial PD such as α-synuclein, PINK1, and Parkin all alter ER-mitochondrial signaling [243–245]. However, the specific consequences of these alterations on PD pathology are still the subject of active investigation [207].

The protein α-synuclein localizes to MAMs [245] and is thought to influence Ca2+ signaling [205, 206] and lipid metabolism [246], ultimately leading to defective ER and mitochondrial function [206].

Whereas wildtype α-synuclein promotes ER-mitochondrial contacts [206], the association of familial PD mutant α-synuclein with MAMs is disrupted. This change may represent one mechanism for compromised MAM structure and function in PD [246].

However, conflicting data suggest that overexpression of either wild-type or mutant α-synuclein can disrupt ER-mitochondrial contacts by binding to VAPB on the ER membrane and interfering with VAPBPTPIP51 interactions [245].

Disruption of this tether complex can impair mitochondrial energetics because it compromises Ca2+ exchange between the two organelles [245]. Similar mechanisms may explain how DJ-1 mutations contribute to early-onset PD [247].

DJ-1 is normally localized to MAMs where it promotes ER-mitochondrial association and facilitates mCa2+ uptake [248]. Mutant DJ-1, as seen in PD, may disrupt MAM structure, ERmitochondrial contacts, mCa2+ uptake, and mitochondrial bioenergetics [249].

In addition, mutations in Parkin and PINK1 may initiate PD pathogenesis via effects at MAMs. PINK and Parkin are recruited to sites of contact between ER and defective mitochondria to coordinate their autophagic clearance [244, 250].

Thus, defective PINK or Parkin may disrupt mitochondrial quality control mechanisms that rely on MAM interactions. Over time, this could impair cellular metabolism and contribute to PD pathology due to the accumulation of dysfunctional mitochondria.

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Mitochondrial structural defects

The mitochondrial structure is determined by a precise balance between mitochondrial fusion and fission and membrane dynamics that are mediated by several proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1), mitochondrial fission factor (MFF), and fission 1 protein [251].

During fasting or starvation, mitochondria tend to fuse [252] due to inhibition of Drp1 by PKA and AMPK [253, 254]. These changes in mitochondrial structure alter respiratory complex assembly and affect the coupling between respiration and ATP synthesis [252], thereby increasing ATP production efficiency when fuel is scarce.

Defective mitochondrial fission and fusion have been implicated in NDDs [251], and abnormal mitochondrial structure and morphology are reported in AD, PD, and HD [255]. Increased mitochondrial fragmentation is often observed in these conditions.

At first consideration, this finding might indicate that neurons in NDDs are well-supplied with metabolic fuels and are fully capable of breaking them down to meet cellular demands for ATP.

However, increased mitochondrial fragmentation may instead reflect or even contribute to metabolic dysfunction in NDDs. Cells adapt to prolonged starvation or chronic defects in metabolism with increased mitophagy, which requires mitochondrial fragmentation [256].

Therefore, excess mitochondrial fragmentation may reflect increased stimuli for mitophagy in NDDs (i.e., impaired fuel utilization and/or mitochondrial dysfunction).

This is perhaps coupled with impairments in the mitophagic machinery and the consequent accumulation of fragmented organelles. According to the model in which mitochondrial fusion enhances ATP production, a shift in mitochondrial dynamics that favors fusion could limit mitochondrial bioenergetics and exacerbate metabolic stress in NDDs.

Several mechanisms are proposed to explain the accumulation of fragmented mitochondria in NDDs. In AD, some reports indicate that net mtDNA content, and ETC protein expression are increased [257, 258], suggestive of a net increase in cellular mitochondrial content. This could occur with an increase in mitochondrial biogenesis and/or a decrease in the clearance of defective, fragmented mitochondria.

For example, APP mutant transgenic mice show upregulation of ETC genes, and Aβ has been shown to increase cellular mtDNA content [258, 259]. On the other hand, other studies report reduced mtDNA content nt, and ETC gene expression in AD brains [260–262].

These disagreements likely reflect differences in the stage of disease examined in these reports. We observed a slight, but non-significant age-dependent decrease in mitochondrial content in AD mice compared to control mice [77].

Finally, experiments in animal models of AD reveal increased S-nitrosylation of Drp1, which causes hyperactivation of Drp1 and excessive mitochondrial fragmentation [263].

Similar effects of hyperactivated Drp1 have been found in postmortem brain samples from AD patients [263]. The accumulation of fragmented mitochondria in PD could result either from primary mutations in PD-associated genes such as PINK and Parkin [264] or from the pathogenic milieu associated with disease progression.

PINK and Parkin cooperate to identify defective mitochondria and target them for degradation via mitophagy [265]. Therefore, impaired clearance and eventual accumulation of dysfunctional mitochondria may be a primary consequence of PD mutations.

PINK1 also controls the structural plasticity of mitochondrial crista junctions via phosphorylation of the inner mitochondrial membrane protein MIC60/mitoflin [266].

Mutation in PINK1 could impact the PINK1-Mic60 interaction and prevent the recruitment of Parkin to damaged mitochondria in PD. Further, excessive reactive nitrogen species (RNS) production in PD may contribute to the accumulation of fragmented mitochondria by modifying the activity of proteins involved in mitochondrial fission/fusion and mitophagy.

For example, S-nitrosylation of Parkin decreases its E3 ubiquitin ligase activity [267], leading to the stabilization of its target, Drp1, which promotes mitochondrial fission [268].

Similarly, S-nitrosylation of PINK1 can impair mitophagy [269] and thereby allow fragmented mitochondria to accumulate. The mechanisms behind altered mitochondrial structure in HD have received less attention.

Studies in a transgenic mouse model expressing mutant human HTT suggest direct transcriptional repression of PGC1α, which could impair mitochondrial biogenesis [270].

Like in AD, increased S-nitrosylation and activation of Drp1 is observed in mouse models of HD [271] and causes excessive mitochondrial fragmentation similar to that seen in HD brains [272].

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