TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration

Abstract

Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer’s disease (AD). Although the pathomechanisms underlining TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.

Introduction

Neurodegenerative diseases are a group of clinically heterogeneous disorders characterized by progressive loss or dysfunction of neurons in the central nervous system (CNS) or peripheral nervous system (PNS) during aging, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) (Lin and Beal, 2006). Although considerable progress has been made to understand how pathological changes in the diseased brain cause neurodegeneration, effective treatments for these devastating diseases are very limited. As a common feature, extracellular or intracellular inclusions containing abnormal accumulation of aggregate-prone proteins characterize many neurodegenerative diseases. In the past decade, TDP-43, encoded by the TARDBP gene, has emerged as a key player in the pathogenesis of diverse neurodegenerative diseases.

TDP-43 has been identified as a major component of the ubiquitinated cytoplasmic inclusions deposited in neurons and glial cells in ALS and FTD (Arai et al., 2006; Neumann et al., 2006). Importantly, TDP-43 gene mutations can cause ALS, together establishing the direct link between TDP-43 and neurodegenerative diseases (Kabashi et al., 2008; Pesiridis et al., 2009; Rutherford et al., 2008; Sreedharan et al., 2008; Van Deerlin et al., 2008). Neurodegenerative diseases associated with aberrant TDP-43 aggregation have been collectively referred to as “TDP-43 proteinopathies”, the term of which is also used to described characteristic histopathological presence of detergent-resistant ubiquitinated, hyperphosphorylated, and truncated species of TDP-43, in addition to its redistribution from the nucleus to cytoplasm (Geser et al., 2009; Mackenzie et al., 2007). Although the formation of cytoplasmic inclusions suggests likely gain of toxic function (Lee et al., 2011), increasing evidence suggests that pathological TDP-43 mediates neurodegeneration through both gain and loss-of-function mechanisms by interrupting multiple pathways including RNA metabolism (Lagier-Tourenne et al., 2010; Polymenidou et al., 2011; Tollervey et al., 2011), protein translation (Buratti and Baralle, 2008; Freibaum et al., 2010), stress-induced response (Colombrita et al., 2009; Dewey et al., 2011; McDonald et al., 2011), autophagy (Bose et al., 2011; Xia et al., 2016), endocytosis (Liu et al., 2017; Schwenk et al., 2016), ubiquitin-proteasome system (UPS) (Hanson et al., 2010; Kim et al., 2009), and mitochondrial function (Wang et al., 2013; Wang et al., 2016; Xu et al., 2010).

TDP-43-linked neurodegenerative diseases are generally multifactorial and involve diverse pathogenic mechanisms such as glutamate excitotoxicity (Li et al., 1997; Sasaki et al., 2000), oxidative stress (Pedersen et al., 1998; Smith et al., 1994), neuroinflammation (Henkel et al., 2004), and mitochondrial dysfunction (Beal et al., 1997; Gibson et al., 1998) in addition to the widely studied TDP-43 proteinopathy. Among them, mitochondrial dysfunction has been extensively studied in the past decade. As prominent early pathological features, mitochondrial abnormalities are closely associated with pathologically related TDP-43 in ALS and FTD patients and experimental models (Izumikawa et al., 2017; Magrane et al., 2014; Salvatori et al., 2018; Wang et al., 2013; Wang et al., 2016). In this review, we first describe the association of TDP-43 with mitochondria, then review in detail the possible mechanisms by which pathological TDP-43 causes mitochondrial abnormalities, and finally discuss future perspectives of mitochondrial related research for TDP-43 proteinopathy.

TDP-43 mitochondrial association

As a member of heterogeneous ribonucleoproteins (hnRNPs) family, TDP-43 is composed of two DNA/RNA recognition and interaction motifs (RRM1, 106–177aa and RRM2, 192–259aa), an N-terminal domain (NTD, 1–102aa), and a carboxyl-terminal glycine-rich domain (CTD, 274–414aa) (Buratti and Baralle, 2001; Kuo et al., 2009). The nuclear localization sequence (NLS, 82–98aa) resides in NTD. Although TDP-43 bears a putative nuclear export sequence (NES, 235–250aa), most recent studies suggest that the nuclear export of TDP-43 is predominantly driven by passive diffusion (Pinarbasi et al., 2018; Winton et al., 2008). The CTD consisting of two prion-like regions flanking the middle hydrophobic fragment, has been demonstrated to undergo liquid-liquid phase separation (LLPS) to facilitate the formation of membrane-less organelles such as RNA and stress granules (Choi et al., 2018; Conicella et al., 2016; Lei et al., 2018; Li et al., 2018; McGurk et al., 2018; Molliex et al., 2015; Sun et al., 2019; Wang et al., 2018a).

Under the physiological condition, the majority of TDP-43 resides in the nucleus and is involved in a wide range of cellular processes such as RNA processing 2018, cryptic splicing (Humphrey et al., 2017; Jeong et al., 2017; Ling et al., 2015), RNA transport (Alami et al., 2014; Pesiridis et al., 2011), and microRNA biogenesis (Buratti et al., 2010; Kawahara and Mieda-Sato, 2012; King et al., 2014) through its DNA/RNA binding ability. Besides its nuclear localization, TDP-43 can also be present in the cytoplasm and co-localize with subcellular compartments such as endoplasmic reticulum (ER) (Li et al., 2015; Walker et al., 2013), mitochondria (Wang et al., 2013; Wang et al., 2016), mitochondria-associated membranes (MAMs) (Stoica et al., 2014), RNA granules (Alami et al., 2014), and stress granules (Colombrita et al., 2009; Liu-Yesucevitz et al., 2010) to regulate ER-mitochondrial tethering, mitochondrial protein translation, mRNA transport, and translation.

Studies by our group and others have independently demonstrated the association of TDP-43 with mitochondria (Fig. 1A). It was firstly reported that exogenously expressed wild type or ALS-associated mutant TDP-43 could be detected in mitochondrial-enriched fractions from NSC-34 motor neuron-like cells (Hong et al., 2012). Consistently, we provided evidence showing the presence of endogenous TDP-43 in highly purified mitochondria from NSC-34 cells without ER contamination (Wang et al., 2013). Using HEK293 cells, human and mouse brain and spinal cord tissues, we further showed that at least a portion of TDP-43 could localize in the inner membrane of mitochondria, and contains several putative mitochondrial import sequences (Wang et al., 2016). However, the following confirmatory studies are largely controversial. For example, TDP-43 was suggested only present in membranes associated with mitochondria in HEK293 or HeLa cells and mouse brains (Kawamata et al., 2017). In contrast, a most recent study using NSC-34 cells reported that full-length and truncated forms of TDP‐43 could differentially reside in the matrix and intermembrane space of mitochondria (Salvatori et al., 2018), while the study using mouse cortical and hippocampal tissue showed truncated but not full-length TDP-43 in mitochondria (Davis et al., 2018) (Fig.1A).

Fig.1. TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration.

(A) TDP-43 mitochondrial association. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; IMS, intermembrane space. (B) Mitochondria are dynamic organelles that undergo continuous fission, fusion, and trafficking, which are critical for the maintenance of mitochondrial function in neurons. The majority of TDP-43 resides in the nuclei and involves in a wide range of cellular processes such as RNA processing, cryptic splicing, RNA transport, and microRNA biogenesis in healthy neurons. (C) In disease-affected neurons, TDP-43 forms inclusions in the cytoplasm, usually accompanied by depletion of nuclear TDP-43. Abnormal mitochondria with altered morphology, inner structure, and OXPHOS activity can be noted in neurons bearing TDP-43 proteinopathy.

There may be several possible reasons for these contradictory findings including methods used to isolate or enrich mitochondria, antibodies used to detect truncated or full-length TDP-43, and the likely variable expression of mitochondrial associated TDP-43. Along this line, it is worthwhile to note that mitochondria associated TDP-43 was found highly phosphorylated in ALS/FTD patient derived neurons or fibroblasts according to our and recent studies (Genin et al., 2018; Wang et al., 2016), together suggesting the likely crucial role of altered posttranslational modifications for TDP-43 mitochondrial accumulation in diseases. Nevertheless, while alternative or novel approaches are to be developed to determine the exact sub-mitochondrial localization of full-length or truncated TDP-43, all previously published studies unanimously support the direct association of TDP-43 with mitochondria. As the characteristic pathological features of TDP-43 proteinopathy include impaired nucleus-cytoplasm-trafficking and aberrant posttranslational modifications of TDP-43, future studies might investigate whether and how ubiquitin ligases, kinases, proteases, and other factors involved in TDP-43 posttranslational modifications and nucleus-cytoplasm-trafficking contribute to TDP-43 mitochondrial association.

TDP-43 and mitochondrial fission and fusion dynamics

Mitochondria are dynamic organelles that undergo continuous fission and fusion (Nunnari et al., 1997). Unopposed fission results in division, while unopposed fusion causes elongation (Bleazard et al., 1999; Sesaki and Jensen, 1999). Studies in the past decade have revealed that mitochondrial fission and fusion dynamics are essential for various aspects of mitochondrial function including respiratory complex assembly (Cogliati et al., 2013), ATP production (Benard et al., 2007), Ca²⁺ homeostasis (Frieden et al., 2004; Szabadkai et al., 2004), and reactive oxygen species (ROS) production (Yu et al., 2006). Mitochondria fission and fusion are tightly controlled by several key regulators including dynamin-like protein 1 (DLP1/Drp1) and its recruiting factors on mitochondria such as Mff and Fis1 (Loson et al., 2013), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy protein 1(OPA1) (Detmer and Chan, 2007). Mitochondrial morphological alterations manifested as fragmented mitochondria with damaged inner membrane structures have been increasingly reported as prominent early features in various major neurodegenerative diseases including ALS (Sasaki et al., 2007) and AD (Wang et al., 2009) (Fig. 1B and 1C).

Xu et al. firstly reported mitochondria aggregation in transgenic mice overexpressing wild type TDP-43 (Xu et al., 2010). And, the subsequent studies observed swollen mitochondria with damaged cristae structures in cultured NSC34 cells expressing ALS-associated mutant TDP-43 (Hong et al., 2012; Lu et al., 2012). Consistently, we and others further demonstrated that mitochondria indeed became fragmented accompanied by loss of mitochondrial inner membrane structure in cultured primary motor neurons or transgenic mice expressing ALS-associated mutant TDP-43 (Gautam et al., 2019; Magrane et al., 2014; Wang et al., 2013). Although ALS patients-derived primary fibroblasts without TDP-43 mutation did not show any mitochondrial morphology changes (Codron et al., 2018), ALS patient-derived lymphoblastoid cell lines or fibroblasts bearing TDP-43 mutation also exhibited damaged and swollen mitochondria (Gautam et al., 2019; Onesto et al., 2016). Noteworthily, the morphology changes seen in TDP-43 experimental models are in good agreement with studies repeatedly reporting altered expression of mitochondria fission and fusion regulators such as Drp1, Fis1, MFN1, and OPA1 (Davis et al., 2018; Joshi et al., 2018; Xu et al., 2010). Although the mechanisms by which TDP-43 regulates mitochondrial dynamics remains elusive, our previous study reported that mutant TDP-43-induced mitochondrial fragmentation could be alleviated by the overexpression of Mfn2, suggesting the likely involvement of Mfn2 dependent fusion. This notion is indeed supported by one most recent study showing the possible physical interaction between TDP-43 and Mfn2 (Davis et al., 2018). However, it is worth noting a puzzling finding in this study: Mfn2 expression was increased rather than reduced by overexpression of wild type TDP-43 in brains, indicating that wild type and mutant TDP-43 may perturb mitochondrial dynamics through different mechanisms.

In addition to neurofibrillary tangles (NFTs) and senile plaques (SPs), cytoplasmic TDP-43 inclusions have been implied as the likely third proteinopathy in patients with AD (James et al., 2016; Uryu et al., 2008). While both Tau and Aβ, the major components of NFTs and SPs, have long been reported to disturb mitochondrial dynamics (Silva et al., 2011), there are limited studies about TDP-43 and mitochondrial dynamics in AD-related experimental models. The recent study reporting increased expression of Mfn2 by TDP-43 also demonstrated that overexpression of wild type TDP-43 caused giant and swollen-structured mitochondria in hippocampal neurons in APP/PS1 transgenic mice for AD (Davis et al., 2018). Although it is still unclear how these findings are reconciled with previous studies showing mitochondrial fragmentation and reduced expression of Mfn2 in AD patients and experimental models (Wang et al., 2009; Wang et al., 2008), the co-existence of multiple pathological features in AD and many other neurodegenerative diseases suggest the likely synergistic effects of TDP-43 and other proteinopathies on mitochondria dynamics, which are relatively unexplored and worthy of further detailed investigation.

TDP-43 and mitochondrial trafficking

In response to various physiological and pathological states, mitochondria are transported by motor-adaptor complexes to sites with bioenergetics requirements, which is vital for neuronal function and survival (Sheng and Cai, 2012). Failure of proper positioning of mitochondria in dendrites or axon terminals has long been implicated in neurodegenerative diseases and proposed as the potential cause of synaptic loss, a prominent early pathological feature well preceding neurodegeneration (Burte et al., 2015). In addition to changed mitochondrial morphology, impaired mitochondria transport was also consistently noted in cell and animal models expressing wild type or disease-associated mutant TDP-43 (Fig. 1B and 1C). In cultured primary motor neurons, overexpression of wild type TDP-43 resulted in impaired mitochondrial anterograde and retrograde transport in both axon and dendrites, which could be exacerbated by ALS-associated mutations (Wang et al., 2013). Unexpectedly, loss of TDP-43 also decreased mitochondrial trafficking in both axons and dendrites similar to TDP-43 overexpression (Wang et al., 2013), indicating the likely involvement of different pathways for TDP-43 mediated mitochondrial transport. Consistent with our findings, loss of fly TDP-43 caused an overall increase in stationary mitochondria in axon, which could be rescued by ectopic expression of fly TDP-43 or human TDP-43 (Baldwin et al., 2016), further suggesting that the mitochondrial trafficking related function of TDP-43 should be conserved between flies and mammals. Importantly, mitochondrial transport defects appeared to be early pathological features of TDP-43 transgenic mice, well proceeding the onset of symptoms and even morphological abnormalities (Magrane et al., 2014). Interestingly, human induced pluripotent stem cells (iPSCs)-derived motor neurons bearing TDP-43 mutation showed drastic slow moving speed at proximal and distal axons in an age-dependent manner without detectable cytoplasmic inclusions or phosphorylated TDP-43 accumulation, further indicating that mutant TDP-43 may cause mitochondrial toxicity independent of proteinopathy (Kreiter et al., 2018).

On the basis of the facts that cytoskeleton is essential for the intracellular transport and positioning of mitochondria, membrane vesicles, and membrane-less RNA granules from neuronal cell body to the distal axonal terminals (Chetta et al., 2015), and that aberrant aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases (Baskaran et al., 2018; Schwenk et al., 2016), it could be anticipated that loss of cytoskeleton integrity caused by pathological TDP-43 might contribute to abnormal mitochondrial transport (Oberstadt et al., 2018). Along this line, by mediating the splicing and translation of mRNA targets, TDP-43 has also been reported to be functionally associated with other microtubule related proteins such as Futsch/MAP1B (Coyne et al., 2014; Godena et al., 2011), NFL (Strong et al., 2007), STMN2 (Klim et al., 2019; Melamed et al., 2019), and Tau (Gu et al., 2017a; Gu et al., 2017b; Lagier-Tourenne et al., 2012). In addition, cytoplasmic TDP-43 has been reported to regulate RNA granules trafficking through microtubule network (Alami et al., 2014). Therefore, although there is no evidence showing TDP-43-regulated mitochondrial transport directly through cytoskeleton, further studies will be interesting to characterize the functional role of reported TDP-43 targets in mediating mutant TDP-43 induced mitochondrial transport defects.

TDP-43 and mitochondrial function

The mitochondrial oxidative phosphorylation system (OXPHOS) utilizes substrates derived from glucose, fatty acids, and amino acids to produce reducing equivalents that are delivered to the respiratory chain to generate adenosine triphosphate (ATP). The respiratory chain consists of four protein complexes (complex I–IV), three of which (I, III, and IV) couple electron transfer to proton pumping across the mitochondrial inner membrane to generate a transmembrane electrochemical potential. The complex V, named ATP synthase, synthesizes ATP from ADP and inorganic phosphate using the energy provided by the proton electrochemical gradient. In addition to generate ATP, mitochondria are also required for a wide range of cellular processes such as the synthesis of key metabolites, Ca²⁺ hemostasis, inflammation and apoptosis. Thus, it is not surprising that mitochondrial functional abnormalities have been extensively studied in many neurodegenerative diseases, including ALS (Beal et al., 1997; Mattiazzi et al., 2002) and AD (Gibson et al., 1998; Ojaimi et al., 1999; Parker et al., 1990) (Fig. 1C).

Several groups have independently reported mitochondrial OXPHOS deficits in TDP-43-associated experimental models. For example, reduced mitochondrial complex I activity and mitochondrial transmembrane potential as well as increased expression of mitochondrial uncoupling protein 2 (UCP2) were firstly noted in NSC-34 cells overexpressing wild type or mutant TDP-43 (Lu et al., 2012). In support of these original findings, we and the recent study in HEK293 or NSC34 cells have independently found that the portion of full-length TDP-43 inside of mitochondria can bind mitochondria-transcribed messenger RNAs (mRNAs) encoding subunits (ND3/6) of OXPHOS complex I to specifically impair its assembly and function (Salvatori et al., 2018; Wang et al., 2019; Wang et al., 2016), whereas truncated TDP-43 lacking the M1 mitochondrial localization sequence is restricted to the intermembrane space and has no effect on ND3/6 expression or mitochondrial function (Salvatori et al., 2018). In addition, TDP-43 has also been reported to maintain mitochondrial function by stabilizing the processing intermediates of mitochondrial polycistronic transcripts encoding the components of electron transport and ribosomal RNAs (Izumikawa et al., 2017). Moreover, ALS patient-derived lymphoblastoid cell line with TDP-43 mutation exhibited perturbed mitochondrial function including increased basal oxygen consumption rate and decreased spare respiratory capacity (SRC), which refer to mitochondrial ability to generate energy (Pansarasa et al., 2018). The role of mitochondria for TDP-43 is further supported by observations that TDP-43 cellular toxicity in yeasts could be altered by manipulating mitochondrial function (Braun et al., 2011; Park et al., 2019). However, despite increasing evidence suggesting mitochondria as targets or mediators of TDP-43 toxicity (Davis et al., 2018; Genin et al., 2018; Hibiki Kawamata, 2017; Izumikawa et al., 2017; Salvatori et al., 2018; Wang et al., 2016; Woo et al., 2017), there are considerable discrepancies as to its impact on mitochondrial function. For example, although reduced mitochondrial membrane potential was observed, oxygen consumption, ATP production, and OXPHOS complex activity remained unchanged in human fibroblasts bearing TDP-43 (Onesto et al., 2016). Similarly, despite altered mitochondrial calcium capacity, oxygen consumption, ATP production, and mitochondrial membrane potential were all reported unchanged in HEK293 cells or transgenic mouse expressing mutant TDP-43 (Kawamata et al., 2017). To resolve these discrepancies, our future investigation might need novel tools or techniques to pinpoint the time-course change of mitochondrial function locally and systematically in different neuronal compartments in response to TDP-43 expression. In addition, as TDP-43 has been reported to interfere in ER–mitochondria associations (Stoica et al., 2014), which are important for calcium homeostasis, lipid metabolism, autophagy, and even protein transport (Pinton, 2018; Wang et al., 2018b), the possible indirect ability of TDP-43 to regulate mitochondrial function should also be considered.

TDP-43 and mitochondrial quality control

Mitochondrial AAA proteases are required for the maintenance of mitochondrial proteostasis and functional integrity (Quiros et al., 2015). And, genetic mutations in mitochondrial AAA proteases have been shown associated with neurodegeneration (Patron et al., 2018). Interestingly, mitochondrial proteases have recently been proposed as an alternative proteostasis mechanism to counteract cytosolic protein aggregates (Ruan et al., 2017). It was shown that during heat shock in yeast, TDP-43 could be imported into mitochondria for degradation by mitochondrial proteases (Ruan et al., 2017). While proteases responsible for mitochondria-imported TDP-43 remain unknown, one most recent study showed that DJ-1, a putative protease localized both in cytoplasm and mitochondria, protected against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation, suggesting that DJ1 may alleviate TDP-43-caused toxicity through degrading both cytoplasmic and mitochondrial TDP-43 (Lei et al., 2018). In addition to the selective turnover of misfolded proteins by mitochondrial proteases, the general mitochondria quality control involves mitophagy, a mechanism by which damaged mitochondria are engulfed in autophagosomes to be degraded through the autophagic-lysosomal pathway (Chen and Chan, 2009). Similar to mitochondrial proteases, mutations in mitophagy-related genes are also closely associated with neurodegenerative disease (Pickrell and Youle, 2015; Youle and Narendra, 2011). Overexpression of TDP-43 has previously been shown to induce mitophagy in NSC34 cells (Hong et al., 2012). And, mutant TDP-43 transgenic mice exhibited mitochondrial accumulations fused with lysosomes, further supporting the possible link between TDP-43 and mitophagy (Gautam et al., 2019). In support of this notion, it has been reported that mitochondrial associated TDP-43 interacts with mitochondrial outer membrane protein prohibitin 2 (PHB2) and voltage-gated dependent anion channel 1 (VDAC1), which are crucial receptors for Parkin-mediated mitophagy (Davis et al., 2018). Although whether TDP-43 is involved in PINK1/Parkin mediated mitophagy remains elusive, Parkin has been reported to mediate poly-ubiquitination of TDP-43, and overexpression of Parkin could reverse TDP-43-induced cell toxicity (Hebron et al., 2014; Hebron et al., 2013; Wenqiang et al., 2014). Likewise, TDP-43 also modulates the expression of Parkin and PINK1, leading to compromised mitochondrial functions and mitophagy (Sun et al., 2018). Augmenting mitophagy by neuronal PINK1 overexpression reduces Aβ pathology and improves mitochondrial and synaptic dysfunction in APP mice (Du et al., 2017). Therefore, it may be anticipated that enhancing mitophagy may be a potential strategy to alleviate TDP-43-induced cytotoxicity.

Conclusions

Like mitochondrial dysfunction (Lin and Beal, 2006), TDP-43 proteinopathy is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and AD. We have reported that the inhibition of TDP-43 mitochondrial localization is sufficient to alleviate mitochondrial dynamic abnormalities, neuronal loss, and behavioral deficits in different mutant TDP-43 transgenic mice (Wang et al., 2016; Wang et al., 2017). Therefore, targeting TDP-43 mitochondrial association may be a promising novel therapeutic approach for neurodegeneration. However, the pathogenic mechanisms linking mitochondrial abnormalities with TDP-43 proteinopathy, and related neurodegeneration are still poorly understood. Consdiering recent discrepant studies reporting the sub-mitochondrial localization of TDP-43 and the interaction of TDP-43 with different mitochondrial pathways, mitochondria-associted TDP-43 or TDP-43 fragments may synergistically mediate mitochondrial and neuronal function through multiple pathways involving but not limited to mitochondrial dynamics, trafficking, bioenergetics, and quality control. As mitochondria are increasingly implicated as critical targets of Aβ, tau, α-synuclein, and many other neurodegenerative disease-associated proteinopathies, mitochondria, therefore, possibly lie at the convergence of a diverse range of proteinopathies. Future research into TDP-43 mitochondrial association in the context of multiple proteinopathies may help us clarify whether and how TDP-43 is physically and functionally associated with mitochondria and contributes to disease progression, and importantly, provide new therapeutic targets for these devastating diseases.

Highlights.

This review describes our current knowledge of the physical and functional association of TDP-43 with mitochondria.