Enhancing Mitophagy to Treat Parkinson’s Disease

Author: Lilly Baker
Editor: Phoebe Tchoua

On November 21, 2023, MTX325 was approved by the Medicines and Healthcare Products Regulatory Agency in the United Kingdom to enter a Phase 1 clinical study for Parkinson’s disease.1 This approval marks the first time that a selective mitophagy enhancer—a drug that promotes the removal of damaged mitochondria—is being tested as a disease-modifying therapeutic. In this post, we (1) discuss how mitochondrial dysfunction contributes to Parkinson’s disease, (2) explore the therapeutic rationale behind mitophagy enhancement, (3) provide a mechanistic overview of ubiquitin-dependent mitophagy, and (4) explain how MTX325 targets this pathway to progress into early clinical development. 

Mitochondrial Dysfunction and Parkinson’s Disease

Cellular health and longevity hinges on mitochondrial function. These dynamic organelles produce 90% of the cell’s energy, synthesize essential metabolites, maintain calcium homeostasis, and even regulate cell death.2 Each cell contains hundreds to thousands of mitochondria, with highly active neurons housing upwards of 2 million.3 Consequently, it should come as no surprise that mitochondrial dysfunction has been linked to the pathophysiology of many chronic diseases, like neurodegeneration (e.g., Parkinson’s disease) and heart failure.4

Parkinson’s disease (PD) is a progressive neurodegenerative disorder where dopamine-producing neurons in the brain’s substantia nigra die off.5 Due to the lack of dopamine, symptoms manifest through various motor troubles and cognitive decline, like tremors, muscle stiffness, depression, and memory loss.6 Age is the primary risk factor for developing PD, with an average onset at 60 years.7 Nearly 10 million people are affected worldwide, and as the population ages, that number is expected to exceed 25 million by 2050.7,8 In the United States alone, the total economic burden of PD is estimated to be $52 billion annually and therapeutic surgery can cost up to $100,000 per person.7 Current treatments approved by the U.S. Food and Drug Administration (FDA), such as levodopa, replenish dopamine levels and help manage symptoms but do not slow disease progression.6 Hence, there is a significant unmet need for disease-modifying therapies.

PD is inherently heterogeneous. Its sporadic and inherited causes, varying clinical presentations, and convoluted pathophysiology have challenged the development of target-/group- and individual-specific disease-modifying therapies.9 However, mounting genetic analyses, post-mortem studies, and functional assays have begun to shed light on mitochondria as a promising therapeutic avenue. 

Autosomal recessive mutations in the genes parkin RBR E3 ubiquitin protein ligase (PRKN) and PTEN-induced kinase 1 (PINK1) make up the majority of inherited early-onset PD cases.5 This is significant because the proteins encoded by these genes facilitate the autophagic clearance of dysfunctional mitochondria, a quality control mechanism called mitophagy. Thus, mutations in PRKN and PINK1 disrupt mitophagy and cause damaged mitochondria to accumulate within cells.

The first time damaged mitochondria were linked to PD was through post-mortem studies on individuals who developed the condition after injecting themselves with synthetic heroin contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).10 MPTP is a potent neurotoxin that disrupts complex I of the electron transport chain, the mitochondria’s energy motor. The discovery of MPTP-induced PD led to major breakthroughs that indicated how the downstream effects of mitochondrial damage—such as reduced adenosine triphosphate (ATP) production and increased reactive oxygen species (ROS)—drive PD progression.11 

The main pathological feature of PD is the buildup of toxic α-synuclein, a protein that forms into insoluble fibrils called Lewy bodies.5 A major problem with α-synuclein accumulation is that it hinders mitochondrial function. The binding of α-synuclein aggregates to mitochondria can exacerbate mitochondrial damage. As a result, ROS production increases and ATP depletes, which can lead to the release of mitochondrial deoxyribonucleic acid (DNA) and subsequent activation of inflammatory pathways. Additionally, calcium homeostasis can become disrupted, which impairs synaptic plasticity (i.e. the ability to strengthen neural connections).12  Together, these events converge to trigger the death of dopaminergic neurons and elicit PD (Figure 1). Given that there are several interconnected PD mechanisms downstream of mitochondrial dysfunction, therapies targeting damaged mitochondria may offer a novel and holistic approach at slowing disease progression.

Figure 1. Mitochondrial dysfunction is a hallmark of Parkinson’s Disease.
Schematic comparing a healthy substantia nigra with normal amounts of dopamine (as shown to the left) versus a substantia nigra that has Parkinson’s disease with depleted amounts of dopamine (as shown to the right). The substantia nigra consists of dopaminergic neurons, and the synapses of these neurons are shown within the boxes. The right synapse illustrates how the death of dopaminergic neurons is driven by various pathogenic mechanisms associated with mitochondrial dysfunction in PD. Damaged mitochondria and substantia nigra are represented as grey. mtDNA: mitochondrial deoxyribonucleic acid. Figure generated by Lilly Baker with BioRender.

Leveraging Mitophagy 

The enormous societal burden associated with PD will continue to grow with no available disease-modifying therapies. Given that research has been highlighting the intricate role of mitochondria in PD, the development of novel therapies is expected to surge. Reflecting the high demand, the global market for mitochondrial-targeted drugs for central nervous system (CNS) indications, including PD, is projected to reach $2.5 billion by 2029. That is a staggering compound annual growth rate of 97% from 2023 to 2029.13

The current attempts to target mitochondrial dysfunction have so far been indirect and have failed to confer long-term clinical benefits.12 For example, in a Phase II trial, the antioxidant coenzyme Q10 (CoQ10) showed promise at high doses (1.2 g/day) in slowing functional decline in early PD patients over two months.14 However, a subsequent 16-month Phase III trial found no significant benefit when 600 patients with early PD received 1.2 g/day, 2.4 g/day, or a placebo.15 A more specific approach was developed with MitoQ, a synthetic mitochondria-targeted version of CoQ10, but its long-term clinical benefit still remains unclear.16,17

Additionally, epidemiological studies revealed that the risk of developing PD was reduced when using glucagon-like peptide-1 (GLP-1) agonists like exenatide.12 More promisingly, exenatide administration enabled neuroprotection in preclinical PD mouse models and improved motor symptoms in a 48-week placebo-controlled clinical trial.18,19 However, a Phase III clinical study funded by Britain’s National Institute for Health and Care Research reported that a 96-week trial testing exenatide in PD patients provided no significant benefit.20 A major factor in these results is that the mechanism of action of exenatide in targeting PD is unclear.20 

The brain is an organ with a high metabolic rate, accounting for 20% of the body’s total energy expenditure.11 Since mature neurons do not divide, they cannot dilute damaged mitochondria through cell division. Instead, neurons must rely on quality control mechanisms like mitophagy to clear dysfunctional mitochondria and remain functional. Moreover, the significant bioenergetic and metabolic requirements of dopaminergic neurons make them especially vulnerable to mitochondrial stress. Consistent with this, in vivo mouse studies using mitophagy reporters have shown that dopaminergic neurons exhibit high mitophagy levels.21 This largely underlies why defective mitophagy has been implicated in synaptic dysfunction in the early pathophysiology of PD.22 Additionally, as mentioned earlier, the genes PINK1 and PRKN are key regulators of mitophagy and are commonly mutated in patients with PD. Given that mitophagy is crucial for neuronal health and deficits in this process are genetically driven, enhancing mitophagy offers a promising therapeutic approach for treating both inherited and sporadic forms of PD. 

Non-selective mitophagy enhancers are currently being pursued as a means of targeting the root cause of mitochondrial dysfunction in PD. In fact, the immunosuppressant rapamycin and the supplement nicotinamide riboside have both shown positive outcomes in preclinical studies and Phase 1 trials.23,24 However, the action of these agents is pleiotropic and not well understood. Similar to exenatide, rapamycin and nicotinamide riboside may encounter challenges in later clinical trials due to the lack of a fully characterized mechanism of action in targeting PD.25

Ubiquitin-Mediated Mitophagy

New targeted therapeutics addressing mitochondria damage are beginning to emerge as our understanding of the molecular components that regulate mitophagy become clearer. The PINK1-Parkin pathway represents the most promising therapeutic avenue due to its highly characterized ubiquitination mechanism. Landmark studies have shown that damaged mitochondria are cleared from the cell through the coordinated activity of the serine/threonine (Ser/Thr) kinase PINK1 and the ubiquitin E3 ligase Parkin (Figure 2).25 This process tags damaged mitochondria with ubiquitin, which enables its recognition and clearance by autophagic machinery. Additionally, ubiquitin-specific peptidase 30 (USP30), a deubiquitylating enzyme, has been identified as a negative regulator of this pathway by removing ubiquitin chains.25  Since PINK1 promotes mitophagy and USP30 inhibits it, both have become key targets for small molecule intervention. Moreover, the PINK1 activator ABBV-1088 (Mitokinin/AbbVie) and the USP30 inhibitor MTX325 (Mission Therapeutics) are both entering Phase 1 clinical trials as the first selective mitophagy enhancers to treat PD.25,26

Figure 2. Overview of Ubiquitin-Mediated Mitophagy.
In ubiquitin-mediated mitophagy, mitophagy activation (shown in the pink box) is initiated by mitochondrial damage, which leads to the accumulation of the Ser/Thr kinase PINK1 on the outer mitochondrial membrane. This activates PINK1 causing it to phosphorylate the ubiquitin E3 ligase Parkin. Once phosphorylated, Parkin becomes activated and ubiquitinates numerous outer mitochondrial membrane (OMM) proteins. When ubiquitin chains accumulate beyond a critical threshold, adaptor proteins like  OPTN are recruited and link ubiquitylated mitochondria to LC3, a key binding protein on phagophores (shown as a blue half-circle). This process promotes lysosomal degradation of the autophagosome-engulfed mitochondria, ultimately preventing mitochondrial dysfunction (shown in the red box) and neurodegeneration (shown in the black box).25 Damaged mitochondria and neuronal death are represented as grey. Figure created by Lilly Baker with Biorender.

MTX325: From Bench to Bedside

In late 2023, the UK-based biotech company Mission Therapeutics (Mission) published a pivotal preclinical study using a mouse model of PD that conveyed the translational capabilities of MTX325. They found that genetic knockdown of USP30 increased CNS mitophagy, protected against dopaminergic neuron loss, and reduced α-synuclein aggregation. More importantly, they found that pharmacological USP30 inhibition via MTX325 similarly showed dose-dependent protection against dopaminergic neuron loss and α-synuclein aggregation, as well as the prevention of inflammatory responses.27

Figure 3. MTX325 mechanism of action
MTX325 is a selective and CNS-penetrant USP30 inhibitor that enhances ubiquitin-mediated mitophagy.27 USP30 is a deubiquitylating enzyme that is localized to the outer mitochondrial membrane and removes ubiquitin chains from damaged mitochondria (shown in grey). By inhibiting USP30, MTX325 promotes the accumulation of ubiquitin chains on dysfunctional mitochondria which facilitates their recognition and clearance. Figures generated by Lilly Baker with BioRender and MTX325 chemical structure24 were created using ChemDraw 22.2.0.

Building on promising preclinical data, Mission launched Phase 1 of its multi-part and adaptive clinical study of MTX325 in March 2024. This first-in-human study enrolled up to 160 adults across the UK, including healthy volunteers and PD patients.26  The trial began with single and multiple dose ascending stages in healthy volunteers and extended to elderly non-PD participants in June 2024 to control for age-related effects. Early data from these cohorts have revealed that MTX325 has a good safety profile, pharmacokinetics, and CNS penetration.28 Backed by funding from The Michael J. Fox Foundation for Parkinson’s Research and Parkinson’s UK, a 28-day dosing of MTX325 in PD patients is expected to begin in early 2025. The goal for this cohort is to observe how MTX325 modulates PD biomarkers, although it’s unclear what specific biomarkers Mission is pursuing.28

The most common limitation to the success of early PD clinical trials is the lack of reliable, inexpensive, and non-invasive biomarkers.29 Without an accurate PD biomarker, tracking target engagement, monitoring disease progression, and optimizing patient stratification is nearly impossible. However, recent data from Mitokinin suggest that mitophagy activation can be detected in cerebrospinal fluid (CSF) and blood plasma by measuring phosphorylated ubiquitin at serine 65 (p-Ser65-Ub) using immunodetection techniques.25,30 Having a molecular readout for mitophagy levels will significantly aid in evaluating early proof of concept for MTX325. Additionally, an α-synuclein seed amplification assay is being developed to quantify α-synuclein aggregation in skin samples, a more accessible tissue than CSF. If MTX325 demonstrates the same ability to reduce α-synuclein aggregation in people with PD as seen in its preclinical studies, then the combined use of p-Ser65-Ub and α-synuclein as biomarkers could potentially expedite its regulatory approval process.25 However, the stage of development for these biomarkers and how they will be integrated into clinical strategy remain unclear.

Despite early clinical uncertainties, small molecule USP30 inhibitors still represent a promising therapeutic approach due to their potential to treat multiple disease indications. Another area of interest is employing mitophagy enhancement to protect kidney health, as this organ also has high metabolic demands and selective sensitivities to mitophagy defects. In fact, the U.S. Food and Drug Administration has approved MTX652, a peripherally-restricted USP30 inhibitor, to enter a phase II clinical trial to treat acute kidney injury following cardiac surgery.31

Thanks to advancements in basic science, we now have a deep understanding of how mitochondria are implicated in a variety of hard-to-treat diseases. But the real challenge lies in successfully translating these insights into the clinic. MTX325 and MTX652 are the first mitophagy enhancers to enter clinical trials; therefore, the utility of mitophagy enhancement as a therapeutic strategy greatly depends on their clinical outcomes. Looking ahead, this field is poised to evolve over the coming years as we gather more clinical data, validate alternative mitophagy targets, and develop new selective agents. Although it’s too early to tell, enhancing mitophagy could revolutionize how we combat chronic diseases— that is, by harnessing our cells’ own quality control mechanisms to restore mitochondrial health. 

References

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  31. Dunmore R, Haines Z, Williams R, et al. Abstract 4135531: The ubiquitin-specific protease 30 inhibitor, MTX652, attenuates cardiac dysfunction and remodelling in a murine model of transverse aortic constriction. Circulation. 2024;150(Suppl_1):A4135531. doi:10.1161/circ.150.suppl_1.4135531

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