A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Abstract

In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca(2+) overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca(2+) load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.

Mitochondria and aging: A role for the mitochondrial transition pore?

“…Two opening states of the pore have been distinguished, a permanent or long‐lasting state which is associated with cell death, and a transient opening state having a physiological role by providing a pathway to release ROS and calcium from mitochondria which is also regulated by CypD (Elrod et al., 2010; Hausenloy, Wynne, Duchen, & Yellon, 2004; Petronilli et al., 1999). The mPTP is now considered to be central in numerous conditions such as heart, brain, or liver ischemia–reperfusion (Friberg & Wieloch, 2002; Halestrap, 2010; Kim, He, Qian, & Lemasters, 2003; Morin, Hauet, Spedding, & Tillement, 2001; Rauen & de Groot, 2004), drug‐induced liver injury (Jaeschke, McGill, & Ramachandran, 2012), age‐related neurodegenerative diseases (Rao, Carlson, & Yan, 2014), and accumulating data imply the mPTP in organ dysfunction occurring during aging (Hepple, 2016; Rocha‐Rodrigues et al., 2013; Toman & Fiskum, 2011). Conversely, caloric restriction, which is a proven strategy to delay aging and age‐related disease (Balasubramanian, Howell, & Anderson, 2017), is associated with the inhibition of mPTP opening (Amigo, Menezes‐Filho, Luévano‐Martínez, Chausse, & Kowaltowski, 2017; Hofer et al., 2009; Kristal & Yu, 1998; Menezes‐Filho et al., 2017).…”

Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

“…were treated with the calcium ionophore A23187, which is a well described inducer of necrotic cell death due to cellular calcium overload and MPTP formation resulting in plasma membrane rupture and LDH release (10,46). We previously reported that A23187 stimulated [ , but we had not monitored cell death (38).…”

“…For example, MPTP formation and necrotic cell death due to calcium accumulation and oxidative stress contribute to ischemia/reperfusion injury of the heart and other organs (9,10). By blocking MPTP formation, CsA protects from myocardial reperfusion injury (15,16).…”

“…ical function in regulating mitochondrial Ca 2ϩ homeostasis, however, its irreversible opening occurs in response to extreme environmental insults or during disease resulting in mitochondria swelling, depolarization, ATP depletion, and plasma membrane permeabilization (10,14). For example, MPTP formation and necrotic cell death due to calcium accumulation and oxidative stress contribute to ischemia/reperfusion injury of the heart and other organs (9,10).…”

Mitochondrial calcium handling during ischemia-induced cell death in neurons

“…Ca 2þ is not the only regulator of PTP and many other factors (oxidative stress, voltage, pH, peptides and a wide array of small molecules) are able to modulate the activity of this pore [66,67,69]. Importantly, several regulators of PTP opening act by modulating the Ca 2þ sensitivity of the pore [66,103]. In addition to being activated by Ca 2þ…”